Note: Descriptions are shown in the official language in which they were submitted.
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AMIDE DERIVATIVES AS PPAR ACTIVATORS
The present invention is concerned with novel phenyl derivatives, their
manufacture, pharmaceutical compositions containing them and their use as
medicaments. The active compounds of the present invention are useful as lipid
modulators and insulin sensitizers.
In particular, the present invention relates to compounds of the general
formula
R5
R4 R R 6
O O ( 7
R~.O 8
R~-x R3
and pharmaceutically acceptable salts and esters thereof, wherein
R' is hydrogen or Cl_7-alkyl;
RZ and R3.are independently from each other hydrogen or Cl_7-allcyl,
R4 and R8 independently from each other are selected from the group consisting
of
hydrogen, Cl_7-alkyl, C3_7-cycloallcyl, halogen, Cl-7-alkoxy- Cl_7-aIlcyl,
CZ_7-alkenyl, CZ_7-alkinyl, fluoro-CI_7-alkyl, cyano-CI_7-alkyl and cyano;
R5, R6 and R7 independently from each other are selected from the group
consisting
of hydrogen, Cl_7-alkyl, C3_7-cycloalkyl, halogen, Cl_7-alkoxy- Cl_7-alkyl,
CZ_7-alkenyl, Ca_7-alkinyl, fluoro-CI_7-alkyl, cyano-CI_7-alkyl and cyano;
and one of R5, R6 and R7 is
y~Yi Ris
X' ~~ (CH
(CR1oR11)m-- 2~~ ya- Y4
wherein
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Xl is selected from the group consisting of
-(CRl4R15), -(CRi4Ris)CH2-, -CH2(CR14 R'S)-, -CH2CH2CH2-,
-(CR14R15)CHaCH2-, -CH2(CR14R15)CH2-, -CH2CH2(CR14Ri5)-,
-CH2CH2CH2CH2-, -(CR14R15)CH2CHaCH2-, -CH2(CR14R15)CH2CH2-,
-CHzCHa(CR14R15)CHZ-, and -CH2CH2CH2(CR14 Rl5)-,
or, in addition,
X' is selected from the group consisting of
-OCH2-, -O(CR'4R15)-, -OCH2CH2-, -O(CR14H)CH2-,
-OCH2 (CR14R15)-, -OCH2CH2CH2-, -O(CR14H)CHzCH2-,
-OCH2(CR14RIS)CH2-, and -OCH2CH2(CR14R")-,
when X2 is -CONR9-; or
Xl is selected from the group consisting of
-OCH2CH2-, -O(CR'4H)CH2-, -OCH2(CR14R15)-,
-OCH2CH2CH2-, -O(CR14H)CH2CH2-, -OCH2(CR14R15)CH2-, and
-OCH2CH2(CR14R15)-, when X2 is -NR9CO-,
XZ is -NR9CO- or -CONR9-;
R9 is selected from the group consisting of hydrogen, Cl-7-alkyl, C3-7-
cycloalkyl,
fluoro-Cl-7-alkyl, hydroxy-C2-7-alkyl, and Ci-7-alkoxy-C2_7-alkyl;
Yl, Y2, Y3 and Y4 are N or C-R12 , whereas none, one or two of Yl, Y2, Y3 and
Y4 are
N and the other ones are C-Rla;
R10 is selected from the group consisting of CI-7-alkyl, C3-7-cycloalkyl,
fluoro-Cl_7-
alkyl, and Ci-7-alkoxy-Ci-7-alkyl;
R" is selected from the group consisting of hydrogen, Cl-7-alkyl, and
Ci-7-alkoxy-Ci-7-alkyl;
R12 independently from each other in each occurance is selected from the group
consisting of
hydrogen, Cl_7-alkyl, C3-7-cycloalkyl, fluoro-Cl-7-allcyl, Cl-7-alkoxy-Cl_7-
alkyl,
hydroxy-Cl-7-alkyl, Ci_7- allcylthio-Cl-7-alkyl, carboxy-Cl_7-alkoxy-Cl_7-
alkyl,
carboxy, carboxy-Ci_7-alkyl, mono- or di-Cl-7-alkyl-amino-Cl-7-alkyl,
Ci-7-alkanoyl-Ci-7-alkyl, CZ-7-alkenyl, and C2-7-alkinyl;
R13 is aryl or heteroaryl;
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R14 is selected from the group consisting of Ci_7-alkyl, C3_7-cycloalkyl,
fluoro-CI_7-
alkyl, and C1.7-alkoxy-Cl_7-alltyl;
R15 is selected from the group consisting of hydrogen, CI_7-alkyl, C3.7-
cycloallcyl,
fluoro-Cl_7-alkyl, and Cl.7-alkoxy-Cl_7-alkyl;
m is 0 orl; and
nis0,1,2or3.
It has been found that compounds of formula I are PPAR activators.
Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear
hormone receptor superfamily. The PPARs are ligand-activated transcription
factors that
1o regulate gene expression and control multiple metabolic pathways. Three
subtypes have
been described: PPARa, PPARS (also known as PPAR(3), and PPARy. PPARS is
ubiquitously expressed. PPARa is predominantly expressed in the liver, kidney
and heart.
There are at least two major isoforms of PPARy. PPARyl is expressed in most
tissues, and
the longer isoform, PPARy2 is almost exclusively expressed in adipose tissue.
The PPARs
modulate a variety of physiological responses including regulation of glucose-
and lipid-
homeostasis and metabolism, energy balance, cell differentiation, inflammation
and
cardiovascular events.
Approximately half of all patients with coronary artery disease have low
concentrations of plasma HDL cholesterol. The atheroprotective function of HDL
was
first highlighted almost 25 years ago and stimulated exploration of the
genetic and
environmental factors that influence HDL levels. The protective function of
HDL comes
from its role in a process termed reverse cholesterol transport. HDL mediates
the
removal of cholesterol from cells in peripheral tissues including those in the
atherosclerotic lesions of the arterial wall. HDL then delivers its
cholesterol to the liver
and sterol-metabolizing organs for conversion to bile and elimination. Data
from the
Framingham study showed that HDL-C levels are predictive of coronary artery
disease
risk independently of LDL-C levels. The estimated age-adjusted prevalence
among
Americans age 20 and older who have HDL-C of less than 35 mg/dl is 16% (males)
and
5.7% (females). A substantial increase of HDL-C is currently achieved by
treatment with
3o niacin in various formulations. However, the substantial side-effects limit
the therapeutic
potential of this approach.
As many as 90% of the 14 million diagnosed type 2 diabetic patients in the US
are
overweight or obese, and a high proportion of type 2 diabetic patients have
abnormal
concentrations of lipoproteins. The prevalence of total cholesterol > 240
mg/dl is 37% in
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diabetic men and 44% in women. The respective rates for LDL-C > 160 mg/dl are
31%
and 44%, respectively, and for HDL-C < 35 mg/dl 28% and 11%, respectively.
Diabetes is
a disease in which a patient's ability to control glucose levels in blood is
decreased
because of partial impairment in response to the action of insulin. Type II
diabetes (T2D)
is also called non-insulin dependent diabetes mellitus (NIDDM) and afflicts 80-
90 % of
all diabetic patients in developed countries. In T2D, the pancreatic Islets of
Langerhans
continue to produce insulin. However, the target organs for insulin action,
mainly
muscle, liver and adipose tissue, exhibit a profound resistance to insulin
stimulation. The
body continues to compensate by producing unphysiologically high levels of
insulin,
1o which ultimately decreases in later stage of disease, due to exhaustion and
failure of
pancreatic insulin-producing capacity. Thus T2D is a cardiovascular-metabolic
syndrome associated with multiple comorbidities including insulin resistance,
dyslipidemia, hypertension, endothelial dysfunction and inflammatory
atherosclerosis.
First line treatment for dyslipidemia and diabetes generally involves a low-
fat and
low-glucose diet, exercise and weight loss. However, compliance can be
moderate, and as
the disease progresses, treatment of the various metabolic deficiencies
becomes necessary
with e.g. lipid-modulating agents such as statins and fibrates for
dyslipidemia and
hypoglycemic drugs, e.g. sulfonylureas or metformin for insulin resistance. A
promising
new class of drugs has recently been introduced that resensitizes patients to
their own
insulin (insulin sensitizers), thereby restoring blood glucose and
triglyceride levels to
normal, and in many cases, obviating or reducing the requirement for exogenous
insulin.
Pioglitazone (ActosTM) and rosiglitazone (AvandiaTM) belong to the
thiazolidinedione
(TZD) class of PPARy-agonists and were the first in their class to be approved
for
NIDDM in several countries. These compounds, however, suffer from side
effects,
including rare but severe liver toxicity (as seen with troglitazone). They
also increase
body weight in patients. Therefore, new, more efficacious drugs with greater
safety and
lower side effects are urgently needed. Recent studies provide evidence that
agonism of
PPAR8 and/or PPAR a would result in compounds with enhanced therapeutic
potential,
i. e. such compounds should improve the lipid profile, with a superior effect
on HDL-C
3o raising compared to current treatments and with additional positive effects
on
normalization of insulin-levels (Oliver et al; Proc Nat Acad Sci USA 2001; 98:
5306-11).
Recent observations also suggest that there is a independent PPARa mediated
effect on
insulin-sensitzation in addition to its well known role in reducing
triglycerides (Guerre-
Millo et al; J Biol Chem 2000; 275: 16638-16642). Thus selective PPARa
agonists,
selective PPAR8 agonists or PPARoc/S co-agonists, optionally with additional
moderate
PPARy agonisme, may show superior therapeutic efficacy without the side-
effects such as
the weight gain seen with pure PPARy agonists.
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The novel compounds of the present invention exceed the compounds known in
the art, inasmuch as they bind to and selectively activate PPARa or coactivate
PPARa
and PPARS simultaneously and very efficiently, and with much improved
pharmacokinetic properties. Therefore, these compounds combine the anti-
dyslipidemic
and anti-glycemic effects of PPARa and PPA12$ activation, and optionally have
an
additional moderate effect on PPARy reinforcing their anti-glycemic potential.
Consequently, HDL cholesterol is increased, triglycerides are lowered (=
improved lipid
profile) and plasma glucose and insulin are reduced (= insulin sensitization).
In addition,
such compounds may also lower LDL cholesterol, decrease blood pressure and
counteract inflammatory atherosclerosis. Furthermore, such compounds may also
be
useful for treating inflammatory diseases such as rheumatoid arthritis,
osteoarthritis, and
psoriasis. Since multiple facets of combined dyslipidemia and the T2D disease
syndrome
are addressed by PPAR tx or S-selective agonists and PPAR8 and a coagonists,
they are
expected to have an enhanced therapeutic potential compared to the compounds
already
known in the art.
The compounds of the present invention further exhibit improved
pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to
illustrate and
define the meaning and scope of the various terms used to describe the
invention herein.
The term "alkyl", alone or in combination with other groups, refers to a
branched
or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to
twenty
carbon atoms, preferably one to sixteen carbon atoms, more preferably one to
ten carbon
atoms.
The term "lower alkyl" or "Cl_7-alkyP", alone or in combination with other
groups,
refers to a branched or straight-chain monovalent alkyl radical of one to
seven carbon
atoms, preferably one to four carbon atoms. This term is further exemplified
by such
radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and
the groups
specifically exemplified herein.
The term "lower alkenyl" or "Cz_7-alkenyl", alone or in combination, signifies
a
straight-chain or branched hydrocarbon residue comprising an olefinic bond and
up to
7, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples
of alkenyl
groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl,
3-butenyl
and isobutenyl. A preferred example is 2-propenyl.
The term "lower alkinyl" or "C2_7-alkinyl", alone or in combination, signifies
a
straight-chain or branched hydrocarbon residue comprising a triple bond and up
to 7,
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preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of
alkinyl
groups are ethinyl, 1-propinyl, or 2-propinyl.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "fluoro-lower alkyl" or "fluoro-CI_7-alkyl" refers to lower alkyl
groups
which are mono- or multiply substituted with fluorine. Examples of fluoro-
lower alkyl
groups are e.g. -CF3, -CH2CF3, -CH(CF3)2 and the groups specifically
exemplified herein.
The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term
"lower-
allcoxy" or "Ci_7-alkoxy" refers to the group R'-0-, wherein R' is lower-
alkyl. Examples of
lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy
lo and hexyloxy. Preferred are the lower-alkoxy groups specifically
exemplified herein.
The term "lower fluoroalkoxy" or "fluoro-Cl_7-alkoxy" refers to lower alkoxy
groups as defined above which are mono- or multiply substituted with fluorine.
Examples of lower fluoroalkoxy groups are e.g. -OCF3i and -OCHZCF3.
The term "alkylthio" refers to the group R'-S-, wherein R' is alkyl. The term
"lower-
alkylthio" or "C1_7-alkylthio" refers to the group R'-S-, wherein R' is lower-
alkyl.
Examples of CI_a-alkylthio groups are e.g. methylthio or ethylthio. Preferred
are the
lower-alkylthio groups specifically exemplified herein.
The term "mono- or di-Cl_7-alkyl-amino" refers to an amino group, which is
mono- or disubstituted with C1_7-alkyl. A mono-Cl_7-alkyl-amino group includes
for
example methylamino or ethylamino. The term "di-CI_7-allcyl-amino" includes
for
example dimethylamino, diethylamino or ethylmethylamino. Preferred are the
mono- or
di-Ci_7-alkylamino groups specifically exemplified herein.
The term "carboxy-lower alkyl" or "carboxy-Cl_7-alkyl" refers to to lower
alkyl
groups which are mono- or multiply substituted with a carboxy group (-COOH).
Examples of carboxy-lower alkyl groups are e.g. -CH2-COOH (carboxymethyl), -
(CH2)2-
COOH (carboxyethyl) and the groups specifically exemplified herein.
The term "alkanoyl" refers to the group R'-CO-, wherein R' is alkyl. The term
"lower-alkanoyl" or "C1.7-allcanoyl" refers to the group R'-O-, wherein R' is
lower-alkyl.
Examples of lower-alkanoyl groups are e.g. ethanoyl (acetyl) or propionyl.
Preferred are
the lower-alkanoyl groups specifically exemplified herein.
The term "cycloalkyl" or "C3_7-cycloalkyP" denotes a saturated carbocyclic
group
containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl or cycloheptyl.
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The term "aryl" relates to the phenyl or naphthyl group, preferably the phenyl
group, which can optionally be mono- or multiply-substituted, particularly
mono- or di-
substituted by halogen, hydroxy, CN, CF3, NOZ, NH2, N(H, lower-alkyl), N(lower-
alkyl)2, carboxy, aminocarbonyl, lower-alkyl, lower fluoro-alkyl, lower-
alkoxy, lower
fluoro-alkoxy, aryl and/or aryloxy. Preferred substituents are halogen, CF3i
OCF3, lower-
alkyl and/or lower-alkoxy. Preferred are the specifically exemplified aryl
groups.
The term "heteroaryl" refers to an aromatic 5- or 6-membered ring which can
comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as
furyl,
pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl,
imidazolyl, or pyrrolyl.
1o The term "heteroaryl" further refers to bicyclic aromatic groups comprising
two 5- or 6-
membered rings, in which one or both rings can contain 1, 2 or 3 atoms
selected from
nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially
hydrogenated
bicyclic aromatic groups such as e.g. indolinyl. A heteroaryl group may have a
substitution pattern as described earlier in connection with the term "aryl".
Preferred
heteroaryl groups are e.g. thienyl and furyl which can optionally be
substituted as
described above, preferably with halogen, CF3, lower-alkyl and/or lower-
alkoxy.
The term "protecting group" refers to groups such as e.g. acyl,
alkoxycarbonyl,
aryloxycarbonyl, silyl, or imine-derivatives, which are used to temporarily
block the
reactivity of functional groups. Well known protecting groups are e.g. tert-
2o butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl or
diphenylmethylene which can be used for the protection of amino groups, or
lower-
alkyl-, 0-trimethylsilylethyl- and 0-trichloroethyl-esters, which can be used
for the
protection of carboxy groups.
"Isomers" are compounds that have identical molecular formulae but that differ
in
the nature or the sequence of bonding of their atoms or in the arrangement of
their
atoms in space. Isomers that differ in the arrangement of their atoms in space
are termed
"stereoisomers". Stereoisomers that are not mirror images of one another are
termed
"diastereoisomers", and stereoisomers that are non-superimposable mirror
images are
termed "enantiomers", or sometimes optical isomers. A carbon atom bonded to
four
nonidentical substituents is termed a "chiral center".
The term "pharmaceutically acceptable salts" embraces salts of the compounds
of
formula (1) with pharmaceutically acceptable bases such as alkali salts, e.g.
Na- and K-
salts, alkaline earth salts, e.g. Ca- and Mg-salts, and ammonium or
substituted
ammonium salts, such as e.g. trimethylammonium salts. The term
"pharmaceutically
acceptable salts" also relates to such salts.
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The compounds of formula (I) can also be solvated, e.g. hydrated. The
solvation
can be effected in the course of the manufacturing process or can take place
e.g. as a
consequence of hygroscopic properties of an initially anhydrous compound of
formula
(I) (hydration). The term pharmaceutically acceptable salts also includes
pharmaceutically acceptable solvates.
The term "pharmaceutically acceptable esters" embraces derivatives of the
compounds of formula (I), in which a carboxy group has been converted to an
ester.
Lower-alkyl, hydroxy-lower-a]kyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl,
mono-
or di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl, pyrrolidino-lower-
alkyl,
lo piperidino-lower-alkyl, piperazino-lower-alkyl, lower-alkyl-piperazino-
lower-alkyl and
aralkyl esters are examples of suitable esters. The methyl, ethyl, propyl,
butyl and benzyl
esters are preferred esters. The methyl and ethyl esters are especially
preferred. The term
"pharmaceutically acceptable esters" furthermore embraces compounds of formula
(I) in
which hydroxy groups have been converted to the corresponding esters with
inorganic or
organic acids such as, nitric acid, sulphuric acid, phosphoric acid, citric
acid, formic acid,
maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,
p-
toluenesulphonic acid and the like, which are non toxic to living organisms.
In detail, the present invention relates to compounds of formula
w
R4 R 6
/ I
O Q '~ I R~ I
01X R.
R2 R3
wherein
RI is hydrogen or Cl_7-alkyl;
R2 and R3 are independently from each other hydrogen or Cl.7-alkyl,
R4 and Rs independently from each other are selected from the group consisting
of
hydrogen, Cl_7-alkyl, C3_7-cycloalkyl, halogen, Cl_7-alkoxy- Cl_7-alkyl,
CZ_7-alkenyl, CZ_7-alkinyl, fluoro-Cl_7-alk-yI, cyano-Cl_7-alkyl and cyano;
R5, R6 and R7 independently from each other are selected from the group
consisting
of hydrogen, Cl_7-alkyl, C3_7-cycloalkyl, halogen, C1_7-alkoxy- Cl_7-alkyl,
C2_7-alkenyl, C2_7-alkinyl, fluoro-CI_?-alkyl, cyano-Cz_7-alkyl and cyano;
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and one of R5, R6 and R7 is
y ~Y1 R13
X (CR10R11)m- (CH2)n y3-Y't
wherein
X' is selected from the group consisting of
-(CR14Ri5), -(CR14Ri5)CH2-, -CH2(CR14Ri5)-, -CH2CH2CH2-,
-(CR'4R15)CH2CHa-, -CH2(CR14R15)CHZ-, -CH2CH2(CR14R15)-,
-CH2CH2CH2CH2-, -(CR14Rls)CH2CH2CH2-, -CH2(CR14R15)CH2CH2-,
-CHaCH2(CR14Rls)CH2-, and -CH2CH2CH2(CR14Ris)-,
or, in addition,
Xl is selected from the group consisting of
-OCH2-, -O(CRI4R15)-, -OCH2CH2-, -O(CR14H)CH2-,
-OCH2(CR'4R15)-, -OCH2CH2CH2-, -O(CR14H)CH2CH2-,
-OCH2(CR14R15)CHa-, and -OCH2CHZ(CR14RI5)-,
when X2 is -CONR9-; or
Xl is selected from the group consisting of
-OCH2CH2-, -O(CR14H)CH2-, -OCH2(CR14Rl5)-,
-OCH2CH2CH2-, -O(CR14H)CH2CHa-, -OCH2(CR14Rl5)CH2-, and
-OCH2CH2(CR14R15)-, when X2 is -NR9CO-,
Xa is -NR9CO- or -CONR9-;
R9 is selected from the group consisting of hydrogen, Cl_7-alkyl, C3_7-
cycloalkyl,
fluoro-Cl_7-alkyl, hydroxy-CZ_7-allcyl, and Cl_7-alkoxy-C2_7-alkyl;
YI, Y2, Y3 and Y4 are N or C-R12 , whereas none, one or two of Y', YZ, Y3 and
Y4 are
N and the other ones are C-R12;
R10 is selected from the group consisting of Cl_7-alkyl, C3_7-cycloalkyl,
fluoro-Cl_7-
alkyl, and Cl_7-alkoxy-Cl_7-alkyl;
Rll is selected from the group consisting of hydrogen, C1_7-allcyl, and
Cl_7-alkoxy-Cl-7-alkyl;
R12 independently from each other in each occurance is selected from the group
consisting of
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hydrogen, C1.7-akl, C3_7-cycloalkyl, fluoro-Cl_7-alkyl, CI_7-alkoxy-Cl_7-
alkyl,
hydroxy-Cl_7-alkyl, Cl_7- alkylthio-Cl_7-alkyl, carboxy-Cl_7-alkoxy-Ct_7-
alkyl,
carboxy, carboxy-Cl_7-alkyl, mono- or di-C1.7-alkyl-amino-CI_7-alkyl,
Cl_7-alkanoyl-Cl_7-alkyl, C2.7-alkenyl, and Ca_7-alkinyl;
R13 is aryl or heteroaryl;
R14 is selected from the group consisting of Q_y-alkyl, C3_ry-cyClOalkyl,
fluoro-Ci_7-
alkyl, and C1_7-alkoxy-Cl_7-alkyl;
Rls is selected from the group consisting of hydrogen, CI_7-alkyl, C3_,-
cycloalkyl,
fluoro-Cl_7-alkyl, and C1_7-alkoxy-Cl.7-alkyl;
m is 0 orl;
n is 0, 1, 2 or 3, and
all pharmaceutically acceptable salts and/or esters thereof.
Preferred compounds of the present invention are for example those, wherein
one
or two of Y', Yz, Y3 and Y4 are N and the other ones are C-R12. Included in
this group are
for example compounds, wherein one of Y', Y2, Y3 and Y4 is N and the other
ones are C-
R1z, thus meaning compounds containing a pyridyl group.
Especially preferred are those compounds of formula I, wherein Y' is N and Ya,
Y3
and Y4 are C-R1z, e. g. compounds of formula I containing the group
R' 2
-N
R 13
R12 R'2
Further preferred compounds of the present invention are those, wherein two of
Y', Y2, Y3 and Y4 are N and the other ones are C-R12, thus meaning compounds
containing a pyrazinyl group or a pyrimidinyl group or a pyridazinyl group.
Especially preferred are compounds of formula I, wherein Y' and Y4 are N and
Y2
and Y3 are C-R12, e. g. compounds of formula I containing the pyrimidinyl
group
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R12
-N
R13
\ N
R12
Also preferred are compounds of formula I, wherein Y' and Y3 are N and Y2 and
Y4
are C-R1a, e. g. compounds of formula I containing the pyrazinyl group
R12
N
RN
T13
2
RlZ is preferably hydrogen, Cl_7-alkyl, C3_7-cycloalkyl, fluoro-Cl_7-alkyl, or
Cl_7-
alkoxy-CI_7-alkyl.
Further preferred compounds of formula I of the present invention are those,
wherein
XZ is -NR9CO-;
lo X' is selected from the group consisting of
-(CRi4Ri5), -(CR14Ris)CH2-, -CH2(CR14R15)-, -CH2CH2CH2-,
-(CR14R15)CHZCHZ-, -CH2(CR'4R15)CH2-, -CH2CH2(CRI4Ri5)-,
-CH2CH2CH2CH22-, -(CR14R15)CHZCHZCH2-, -CH2(CR14R15)CH2CH2-,
-CH2CH2(CR14RIS)CH2-, -CH2CH2CH2(CR14R15)-,
-OCH2CH2-, -O(CR14H)CH2-, -OCH2(CR14R15)-,
-OCH2CH2CH2-, -O(CR14H)CH2CHZ-, -OCH2(CR14R15)CH2-, and
-OCH2CH2(CR14R15)-;
R9 is selected from the group consisting of hydrogen, Cl_7-alkyl, C3_7-
cycloalkyl,
fluoro-C1_7-alkyl, hydroxy-Ca_7-allcyl, and Cl_7-alkoxy-C2_7-alkyl;
2o R14 is selected from the group consisting of Cl_7-alkyl, C3_7-cycloalkyl,
fluoro-CI_7-alkyl,
and Cl_7-alkoxy-Cl_7-alkyl; and
R15 is selected from the group consisting of hydrogen, C2_7-alkyl, C3_7-
cycloalkyl,
fluoro-Cl_7-alkyl, and Cl_7-alkoxy-Cl_7-alkyl.
Within this group, those compounds are more preferred, wherein R14 is Cl_7-
alkyl,
preferably methyl or ethyl, and R15 is hydrogen. Especially preferred are
those
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compounds of formula I, wherein Xl is selected from the group consisting of -
CH(CH3)-,
-CH(C2H5)-, -CH2-CH(CH3)-, -OCH2CH2- and -O-(CHCH3)-CH2-.
Another group of preferred compounds of formula I are those, wherein
X2 is -CONR9-;
X' is selected from the group consisting of
-(CR14R15)' -(CR14R15)CH2-, -CHa(CR14R15)-, -CH2CH2CH2-,
-(CR14R15)CH2CHa-, -CH2(CR14Rls)CH2-, =CH2CH2(CR14R15)-,
-CH2CH2CH2CH2-, -(CR14R15)CH2CH2CH2-, -CH2(CR14R1$)CH2CH2-,
-CH2CH2(CR14R15)CH2-, -CH2CHZCHa(CR14R15)-,
-OCH2-, -O(CR14R15)-, -OCH2CH2-, -O(CR14H)CHZ-,
-OCH2(CR14R15)-, -OCH2CH2CH2-, -O(CR14H)CHZCH2-,
-OCH2(CR14R15)CH2-, and -OCH2CHZ(CR14R15)-;
R9 is selected from the group consisting of hydrogen, Cl_7-alkyl, C3_7-
cycloaIlcyl,
fluoro-C1.7-a1ky1, hydroxy-Ca_7-allryl, and Cl_7-alkoxy-C2_7-alkyl;
R14 is selected from the group consisting of Cl_7-alkyl, C3_7-cycloalkyl,
fluoro-Cl_7-alkyl,
and Cl_7-alkoxy-Cl_7-alkyl; and
R15 is selected from the group consisting of hydrogen, Cl_7-allcyl, C3.7-
cycloalkyl,
fluoro-Cl_7-alkyl, and Cl.7-alkoxy-Cl.7-alkyl.
Within this group, those compounds are more preferred, wherein R14 is Cl_7-
alkyl,
preferably methyl or ethyl, and R15 is hydrogen. Especially preferred are
those
compounds of formula I, wherein X2 is -CONR9- and Xl is selected from the
group
consisting of
-CH(CH3)-, -CH2CH2CH2-, -CH(CH3)CH2-, -OCH2-, and -OCH(CH3)-.
Especially preferred are compounds of formula I of the present invention,
wherein
R9 is hydrogen.
Also preferred are compounds of formula I according to the invention, wherein
Xl is selected from the group consisting of
14R15), 14 15 14 R15
-(CR -(CR R )CH2-, -CHZ(CR )-, -CH2CH2CH2-,
-(CR14R15)CH2CH2-, -CH2 (CR14R15)CH2-, -CH2CH2(CR14R15)-,
-CH2CH2CH2CH2-, -(CR14R15)CHZCHzCHa-, -CH2(CR14R15)CH2CH2-,
-CH2CH2(CR14R15)CH2-, and -CH2CH2CH2(CR14Rl5)-;
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R14 is C1_7-alkyl and R15 is hydrogen.
Another group of preferred compounds of the present invention are those,
wherein
Y', Y2, Y3 and Y4 are C-R12.
Rla is preferably independently selected from the group consisting of
hydrogen, Cl_
7-alkyl, C3_7-cycloalkyl, fluoro-Cl_7-alkyl, or Cl_7-alkoxy-Cl_7-alkyl. Most
preferred are
those compounds, wherein R12 is hydrogen.
Preferred are furthermore compounds of formula I of the present invention,
wherein R6 is
y-~% 1
Y R13
-Y
\X1 (CR1oR11)m . r (CH2)n Y3
io and R4, R$, R7 and R8 independently from each other are selected from
hydrogen or Cl_7-
alkyl.
These compounds have the formula I-A:
R5 R13
R XI-1 2~.(CRIoRzI) \
X m'~(CH2). ~-'('
O O R7
R 8
~ R
O R2 XR
I-A
Also preferred are compounds of formula I according to the invention, wherein
R5
or R7 is
y~-%Y1 R13
2
\X1"x~ r (CH ) \ -~
(CR1oR11) 2 n ~
m
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These compounds have the formula I-B or I-C:
yi=Y' ,s
X R
2 \~
,/-X\ ' (CHZ)~ - ~
(CR,oRõ)m Ys
R4 / Re
O 0 ~ I R'
R ~.O_Rs
R2/ \R3
I-B or
R5
R4 RB y~-YIrR1s
p O 'õ -- (CHz)ny3-1(4
X (CR,oR)m
RO RB
R2 R3
I-C
Furthermore, compounds of formula I, wherein R' is hydrogen, are preferred.
Compounds of formula I, wherein R2 and R3 independently from each other are
hydrogen or methyl, are also preferred. Also preferred are compounds of
formula I,
wherein at least one of RZ and R3 is methyl. Even more preferred are compounds
of
formula I, wherein RZ and R3 are methyl.
The integer m is 0 or 1. Preferred are compounds of formula I, wherein m is 0.
The integer n is 0, 1, 2 or 3. Preferred are compounds of formula I, wherein n
is 0.
However, compounds of formula I, wherein n is 1 are also preferred.
Compounds of formula I, wherein R13 is aryl, are preferred. More preferred are
those compounds of formula I, wherein Rt3 is unsubstituted phenyl or phenyl
substituted
with one to three groups selected from Cl_7-alkyl, Cl_7-alkoxy, halogen,
fluoro-Cl_7-alkyl,
fluoro-Cl_7-alkoxy and cyano, with those compounds, wherein R13 is phenyl
substituted
with halogen, fluoro-Cl_7-alkyl or fluoro-Cl_7-alkoxy, being particularly
preferred.
Examples of preferred compounds of formula I are the following:
[rac] -2- [4-(1-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino} -ethyl)-2-methyl-phenoxy] -2-methyl-propionic acid,
[rac]-2-[4-(1-{[4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-ethyl)-2-methyl-phenoxy] -2-methyl-propionic acid,
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(rac] -2-methyl-2-(2-methyl-4-{ 1- [ ( 3'-trifluoromethyl-biphenyl-4-carbonyl)-
amino] -
ethyl}-phenoxy)-propionic acid,
[rac] -2-methyl-2-(2-methyl-4- { 1- [ (4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino] -
ethyl}-phenoxy)-propionic acid,
[rac]-2-methyl-2-(2-methyl-4-{ 1-[2-methyl-6-(4-trifluoromethyl- phenyl)-
pyridin-3-
ylcarbamoyl] -ethoxy}-phenoxy)-propionic acid,
[rac]-2-{4- [ 1-(biphenyl-4-ylcarbamoyl)-ethoxy] -2-methyl-phenoxy}-2-methyl-
propionic acid,
[rac] -2-(4-{ 1- [4-cyclopropyl-2- (4-trifluoromethyl-phenyl)-pyrimidin-5-
ylcarbamoyl] -
1o ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid,
[ rac] -2-methyl-2-{ 2-methyl-4- [ 1-(3'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethoxy] -
phenoxy}-propionic acid,
[rac] -2-methyl-2-{ 2-methyl-4- [ 1-(4'-trifluoromethyl-biphenyl-3-
ylcarbamoyl)-ethoxy] -
phenoxy}-propionic acid,
2-methyl-2-(2-methyl-4-{ [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoyl]-methraxy}-phenoxy)-propionic acid,
2-[4-(biphenyl-4-ylcarbamoylmethoxy)-2-methyl-phenoxy] -2-methyl-propionic
acid,
2-(4-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl] -
methoxy}-2-methyl-phenoxry)-2-methyl-propionic acid,
2o 2-methyl-2-{2-methyl-4-[(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
methoxy]-
phenoxy}-propionic acid,
2-methyl-2- {2-methyl-4- [ (4'-trifluoromethyl-biphenyl-3-ylcarbamoyl)-
methoxy] -
phenoxy}-propionic acid,
2-methyl-2-(4- {3- [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoyl] -
propyl} -phenoxy) -propionic acid,
2-(4-{3- [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbarnoyl]
-
propyl}-phenoxy)-2-methyl-propionic acid,
2-methyl-2-{4- [3-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-propyl] -
phenoxy}-
propionic acid,
3o 2-methyl-2-{4- [3-(4'-trifluoromethyl-biphenyl-3-ylcarbamoyl)-propyl] -
phenoxy}-
propionic acid,
2-methyl-2- [2-methyl-4-(2-{ [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-
carbonyl] -amino}-ethoxy)-phenoxy] -propionic acid,
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2-[4-(2-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl] -
amino}-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid,
2-methyl-2-[2-methyl-4-(2-{ [4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-
pyrimidine-5-carbonyl] -amino}-ethoxy)-phenoxy] -propionic acid,
2-[4-(2-{[4-methoxytnethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-
amino}-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid,
2- [4-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl] -
acetylamino}-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid,
2-methyl-2-(2-rnethyl-4-{2- [ (4'-trifluoromethyl-biphenyl-4-carbonyl) -amino]
-ethoxy}-
1o phenoxy)-propionic acid,
2-methyl-2-(2-methyl-4-{2- [ (3'-trifluoromethyl-biphenyl-4-carbonyl) -amino] -
ethoxy}-
phenoxy)-propionic acid,
2- [4-(2-{ [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl] -
amino}-
ethoxy)-2-rnethyl-phenoxy]-2-methyl-propionic acid,
[rac] -2- [4-(2-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-1-methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid,
[rac] -2-[4-(2-{ [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-1-methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{ 1-methyl-2-[ (3'-trifluorornethyl-biphenyl-4-
carbonyl)-
2o amino] -ethoxy} -phenoxry)-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{ 1-methyl-2- [ (4'-trifluoromethyl-biphenyl-4-
carbonyl)-
amino]-ethoxy}-phenoxy)-propionic acid,
[rac] -2- [4-(2-{ [4-cyclopropyl-2- (4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid,
[rac]-2-[4-(2-{[4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{ 2- [ (3'-trifluoromethyl-biphenyl-4-carbonyl)-
amino] -
propyl}-phenoxy)-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{ 2- [ (4'-trifl.uoromethyi-biphenyl-4-carbonyl)-
amino] -
propyl}-phenoxy)-propionic acid,
[rac] -2-[4-(1-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino } -propyl)-2-methyl-phenoxy] -2-methyl-propionic acid,
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[rac]-2-[4-(1-{ [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino]-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid,
[rac] -2-methyl-2- (2-methyl-4-{ 1- [ (3'-trifluoromethyl-biphenyl-4-carbonyl)-
amino] -
propyl}-phenoxy)-propionic acid,
[rac]-2-methyl-2-(2-methyl-4-{ 1-[(4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-
propyl}-phenoxy)-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{ 1-methyl-2- [2-methyl-6-(4-trifluoromethyl-
phenyl)-
pyridin-3-ylcarbamoyl] -ethyl}-phenoxy)-propionic acid,
[rac] -2-(4-{ 2- [4-cyclopropyl-2-(4-trifluorornethyl-phenyl)-pyrimidin-5-
ylcarbamoyl] -1-
io methyl-ethyl}-2-methyl-phenoxy)-2-methyl-propionic acid,
[rac] -2-rnethyl-2-{2-methyl-4- [ 1-methyl-2-(4'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethyl] -phenoxy}-propionic acid,
[rac] -2-methyl-2-{2-methyl-4- [ 1-methyl-2-(3'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethyl] -phenoxy}-propionic acid,
[rac]-2-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylcarbarnoyl]-
ethyl}-2-methyl-phenoxy)-2-methyl-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{ 1- [2-methyl-6-(4-trifluoromethyl-phenyl)-
pyridin-3-
ylcarbamoyl] -ethyl}-phenoxy)-propionic acid,
[rac] -2-methyl-2-{2-methyl-4- [ 1-(4'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
ethyl] -
phenoxy}-propionic acid,
[rac] -2-methyl-2-{ 2-methyl-4- [ 1-(3'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethyl] -
phenoxy}-propionic acid, and
[rac] -2-methyl-2- [2-methyl-4-(1-{ [2-(4-trifluoromethoxy-phenyl)-4-
trifluorornethyl-
pyrimidine-5-carbonyl] -amino}-ethyl)-phenoxy] -propionic acid.
Particularly preferred compounds of formula I of the present invention are the
following:
[rac] -2- [4- (1-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-ethyl)-2-methyl-phenoxy] -2-methyl-propionic acid,
[rac] -2-methyl-2- (2-methyl-4-{ 1- [ (3'-trifluoromethyl-biphenyl-4-carbonyl)
-amino] -
ethyl}-phenoxy)-propionic acid,
[rac] -2-(4-{ 1- [4-cyclopropyl-2-(4-trifluoromethyl-phenyl) -pyrimidin-5-
ylcarbamoyl] -
ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid,
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2-methyl-2- { 2-methyl-4- [ ( 3' -trifluoromethyl-biphenyl-4-ylcarbamoyl)-
methoxy] -
phenoxy}-propionic acid,
2-(4-{3- [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrirnidin-5-ylcarbamoyl]
-
propyl}-phenoxy)-2-methyl-propionic acid,
2- [4-(2-{ [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl] -
amino}-
ethoxy)-2-methyl-phenoxy] -2-methyl-propionic acid,
[rac] -2- [4-(2-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid,
j rac] -2-methyl-2-(2-methyl-4-{ 1- [ (4'-trifluorornethyl-biphenyl-4-
carbonyl)-amino] -
1o propyl}-phenoxy)-propionic acid,
[rac] -2-methyl-2-(2-methyl-4-{l-methyl-2- [2-methyl-6-(4-trifluoromethyl-
phenyl) -
pyridin-3-ylcarbamoyl] -ethyl}-phenoxy)-propionic acid, and
[rac] -2-methyl-2-{2-methyl-4- [ 1-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
ethyl] -
phenoxy}-propionic acid.
Especially preferred are also the following compounds of formula I of the
present
invention:
[rac] -2- [4-(1-{ [4-cyciopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-amino}-ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid,
[rac] -2-(4- { 1- [4-cyclopropyl-2- (4-trifluoromethyl-phenyl)-pyrimidin-5-
ylcarbamoyl] -
2o ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid,
2-(4-{ 3- [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]
-
propyl}-phenoxy)-2-methyl-propionic acid,
2-[4-(2-{ [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl] -
arnino}-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid, and
[rac]-2-[4-(2-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-propyl)-2-methyl-phenoxy] -2-methyl-propionic acid.
Furthermore, the pharmaceutically acceptable salts of the compounds of formula
I
and the pharmaceutically acceptable esters of the compounds of formula I
individually
constitute preferred embodiments of the present invention.
Compounds of formula I can have one or more asymmetric carbon atoms and can
exist in the form of optically pure enantiomers, mixtures of enantiomers such
as, for
example, racemates, optically pure diastereoisomers, mixtures of
diastereoisomers,
diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The
optically
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active forms can be obtained for example by resolution of the racemates, by
asymmetric
synthesis or asymmetric chromatography (chromatography with a chiral adsorbens
or
eluant). The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula I in this
invention
may be derivatised at functional groups to provide derivatives which are
capable of
conversion back to the parent compound in vivo. Physiologically acceptable and
metabolically labile derivatives, which are capable of producing the parent
compounds of
general formula I in vivo are also within the scope of this invention.
A further aspect of the present invention is the process for the manufacture
of
1o compounds of formula I as defined above, which process comprises
a) reacting a compound of formula
R5
R4 R6
~
~ ' R7 IT
R ~C R8
R2 R3
wherein R' is Cl_7-allcyl, R2 to R8 are as defined above and one of R5, R6or
R'
is -X'-COOH,
with a compound of formula
R 9 Y~=Y1 R1s
~ III
H(CH ) Y'~
2 n 1(3-
((;R10R11)m_
wherein Y' to Y4, R9, Rlo, R", R13 , m and n are as defined above,
to obtain a compound of formula
R$
R 6
R
4 R
R 1 0 1 ( O ~ I 0 R 8
R2 R3
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wherein one of R5, R6 and W is
R9 1
Y2iY Ris
Xi
(CR1oR11)_ (CH2)n Y3-Y4
m
O
and wherein R' is Cl_7-allcyl and X', Y' to Y4, R2 to R13 and m and n are as
defined
above,
and optionally hydrolysing the ester group to obtain a compound of formula I-
1,
wherein R' is hydrogen;
or, alternatively,
b) reacting a compound of formula
R5
R4 R 6
~
0 O R7 IV
1
R --a R$
R2 R3
wherein R' is Cl_7-aIkyl, R2 to R8 are as defined above and one of R5, R6or R7
is -X'-NHR9, wherein Xl and R9 are as defined above,
with a compound of formula
Y2%Y Ris
O .\
~(CR1OR11)m_ (CH2)n ys-Y'~
HO
wherein Y' to Y4, RIo, R", R13 , m and n are as defined above,
to obtain a compound of formula
R 5
R~ R 6
/ '
O O ~ R7 1-2
R'-~~ Rs
R2 R3
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wherein one of R5, R6 and R7 is
0 Y~'%Y1 R1s
C'iF { -
(CRtoR1i)m-- ( 2)n ys
19 Ya
R
and wherein R' is Cl_7-alkyl and X', Y' to Y4, Ra to R13 and m and n are as
defined
above,
and optionally hydrolysing the ester group to obtain a compound of formula 1-
2,
wherein R' is hydrogen.
As described above, the compounds of formula (I) of the present invention can
be
used as medicaments for the treatment and/or prevention of diseases which are
modulated by PPARS and/or PPARa agonists. Examples of such diseases are
diabetes,
1o particularly non-insulin dependent diabetes mellitus, increased lipid and
cholesterol
levels, particularly low HDL-cholesterol, high LDL-cholesterol, or high
triglyceride levels,
atherosclerotic diseases, metabolic syndrome, syndrome X, obesity, elevated
blood
pressure, endothelial dysfunction, procoagulant state, dyslipidemia,
polycystic ovary
syndrome, inflammatory diseases (such as e.g. Crohn's disease, inflammatory
bowel
disease, colitis, pancreatitis, cholestasis/fibrosis of the liver, rheumatoid
arthritis,
osteoarthritis, psoriasis and other skin disorders, and diseases that have an
inflammatory
component such as e.g. Alzheimer's disease or impaired/improvable cognitive
function)
and proliferative diseases (cancers such as e.g. liposarcoma, colon cancer,
prostate
cancer, pancreatic cancer and breast cancer). The use as medicament for the
treatment of
low HDL cholesterol levels, high LDL cholesterol levels, high triglyceride
levels, metabolic
syndrome and syndrome X is preferred.
The invention therefore also relates to pharmaceutical compositions comprising
a
compound as defined above and a pharmaceutically acceptable carrier and/or
adjuvant.
Further, the invention relates to compounds as defined above for use as
therapeutically active substances, particularly as therapeutic active
substances for the
treatment and/or prevention of diseases which are modulated by PPAR8 and/or
PPARa
agonists. Examples of such diseases are diabetes, particularly non-insulin
dependent
diabetes mellitus, increased lipid and cholesterol levels, particularly low
HDL-cholesterol,
high LDL-cholesterol, or high triglyceride levels, atherosclerotic diseases,
metabolic
syndrome, syndrome X, obesity, elevated blood pressure, endothelial
dysfunction,
procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory
diseases such
as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder,
and proliferative
diseases.
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In another embodiment, the invention relates to a method for the treatment
and/or
prevention of diseases which are modulated by PPARS and/or PPARa agonists,
which
method comprises administering a compound of formula (I) to a human or animal.
Preferred examples of such diseases are diabetes, particularly non-insulin
dependent
diabetes mellitus, increased lipid and cholesterol levels, particularly low
HDL-cholesterol,
high LDL-cholesterol, or high triglyceride levels, atherosclerotic diseases,
metabolic
syndrome, syndrome X, obesity, elevated blood pressure, endothelial
dysfunction,
procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory
diseases such
as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder,
and proliferative
diseases.
The invention further relates to the use of compounds as defined above for the
treatment and/or prevention of diseases which are modulated by PPARS and/or
PPARa
agonists. Preferred examples of such diseases are diabetes, particularly non-
insulin
dependent diabetes mellitus, increased lipid and cholesterol levels,
particularly low HDL-
cholesterol, high LDL-cholesterol, or high triglyceride levels,
atherosclerotic dnseases,
metabolic syndrome, syndrome X, obesity, elevated blood pressure, endothelial
dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome,
inflammatory
diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other
skin disorder,
and proliferative diseases.
In addition, the invention relates to the use of compounds as defined above
for the
preparation of medicaments for the treatment and/or prevention of diseases
which are
modulated by PPARS and/or PPARa agonists. Preferred examples of such diseases
are
diabetes, particularly non-insulin dependent diabetes mellitus, increased
lipid and
cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, or
high
triglyceride levels, atherosclerotic diseases, metabolic syndrome, syndrome X,
obesity,
elevated blood pressure, endothelial dysfunction, procoagulant state,
dyslipidemia,
polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis,
osteoarthritis, psoriasis and other skin disorder, and proliferative diseases.
Such
medicaments comprise a compound as defined above.
The compounds of formula I can be manufactured by the methods given below, by
the methods given in the examples or by analogous methods. Appropriate
reaction
conditions for the individual reaction steps are known to a person skilled in
the art.
Starting materials are either commercially available or can be prepared by
methods
analogous to the methods given below, by methods described in references cited
in the
text or in the examples, or by methods known in the art.
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The synthesis of compounds with the general structure I, particularly
compounds
according to formula Ia to Ih, are described in scheme 1 to scheme 3. Scheme 4
describes
the synthesis of intermediates not covered by schemes 1, 2 and 3. Scheme 5 to
scheme 8
describe the synthesis of synthons 10 and I1 (scheme 1), of synthon 10 (scheme
2) and of
synthon 10 (scheme 3).
The synthesis of compounds with the general structure I, particularly
compounds
according to formula Ia and lb with Xl beginning with an oxygen atom can be
accomplished according to scheme 1. Substituents R, R' correspond to
substituents as
defined in detail in the claims.
Hydroxy aldehydes or hydroxy aryl alkyl ketones I are known or can be prepared
by methods known in the art. Reaction of phenols 1 with alpha halo esters of
formula 2
in the presence of a base like potassium or cesium carbonate in solvents like
acetone,
methyl-ethyl ketone, acetonitrile or N,N-dimethylformamide in a temperature
range
between room temperature and 140 C leads to the corresponding ether compounds
3
(step a). Baeyer Villiger oxidation e. g. with meta chloro perbenzoic acid in
a solvent like
dichloromethane, leads to compounds 4 (step b). Phenols 4 can react with
protected
amino alcohols 5, e. g. via Mitsunobu-reaction, with triphenylphosphine and di-
tert-
butyl-, diisopropyl- or diethyl-azodicarboxylate as reagents; this
transformation is
preferably carried out in a solvent like toluene, dichloromethane or
tetrahydrofurane at
ambient temperature followed by optional N-alkylation (e. g. sodium hydride
and a
reactive alkyl halogenide/mesylate or triflate in a solvent like N,N-
dimethylformamide)
and deprotection (e. g. TFAICH2Cla, or HCl in dioxane at 0 C to RT) leading to
amino
compounds 8 (steps c and d). Alternatively, phenols 4 can react with synthons
6 or 7, if a
free hydroxy group is present e. g. via Mitsunobu-reaction; alternatively, if
they carry a
halide, mesylate, tosylate or triflate moiety, the synthons 6 or 7 can be
reacted with
phenols 4 in solvents like N,N-dimethylformamide, dimethylsulfoxide,
acetonitrile,
acetone or methyl-ethyl ketone in the presence of a weak base like cesium or
potassium
carbonate at a temperature ranging from room temperature to 140 C, preferably
around
50 C to yield the corresponding protected ether compounds (step e).
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Scheme 1
R5 AIkyUH o RS AIkyIM
4 Rt-, ~Halide or Tdttate a
R / l O 2 R= R~ O R O
7 O R7
HO R R a RO2X s
R R3 R
3
b
R5
R4 OH
R O O I R'
'O
RB
4 HO/Hal~ AlkyUtert.butyl
R2 R3
(CRR')t~ O
H 6
HO., i O
(CRR't.s ~ ! or
H H
/Prot.
p -I
c, d 9 HOMaI~ 0
(CRR'),,
7
R$
H
R 4 0- ---,-N. R s O
(CRR')2-3 R
a ,~
O O ~ I R7 R / O~(CRR')~ 3 OH
R O
I
Rz R3 R8 R\ O ~ R~
O Re
8 R2 R3
9
YiY,
R,9
0 ~
h HpIk(CR,oRõ)m=-(CHz)"~\y.-Y' Yt
Yz= ts
H
1 Re_,N,_(CRtoRt,)m (CHz)a ~Yg-Y'
, 11
yz=Y' ts
OI, 1
R5 N---'~ (CHz)n \~-Y
(CRtoRtt)' ~- m
R (CRR)ta R9
t I j p3 R ~ 0 R R~OJ'/~~ e RS t) '
R R R Ra O~ (CRR' N~(CRtoRit) ' (CH2),
/ I )t,3
Ia ~ R~ R9
R~ ~p
O f~ Re
Rz R9 Ib
Depending on the synthon used, standard deprotection, or standard deprotection
followed by oxidation yield acids 9 (step f, g) (e. g. Swern oxidation to the
aldehyde:
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oxalyl chloride / dimethylsulfoxide / triethylamine in dichloromethane, -78 C
to room
temperature; followed by oxidation to the acid with sodium chlorite, sodium
dihydrogenphosphate-dihydrate in tert-butanol / water 2:1 in the presence of 2-
methyl-
2-butene at room temperature). Amines 8 or acids 9 can be chiral and can
optionally be
separated into optically pure antipodes by methods well known in the art, e.
g. by
chromatography on a chiral HPLC column. Condensation of amines 8 or acids 9
with
acids 10 or amines 11 can be performed using well known procedures for amide
formation, such as use of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-
hydrochloride and optionally 4-dimethylamino-pyridine in dichloromethane at
temperatures between 0 C and room temperature yielding compounds Ia (step h)
or lb
(step i).Those can optionally be hydrolyzed according to standard procedures,
e. g. by
treatment with an alkali hydroxide like LiOH or NaOH in a polar solvent
mixture like
tetrahydrofurane/ethanol/water to give carboxylic acids Ia or Ib. In case Rl
is equal to
tert-butyl, treatment with e. g. trifluoroacetic acid, anisole in a solvent
like
dichloromethane between room temperature and the reflux temperature of the
solvents
yields carboxylic acids Ia or lb.
An analogous reaction scheme with the same reaction sequences applies for the
isomeric compound series leading to compounds of general formula I,
particularly
compounds according to formula Ic or Id.
0 y ~Y R,a
R 5 \ 0 ~ (CRR'),-s-Nk(CR,oRõ)'(CH2)õ y3-T
m
4 R6 R9
R /
~
~ ~ ~ R5 or R7 Ic
= f
t O R or YY R,s
1 ~( s I
cR2/ \R3 R 0- ~ ~ (CR,oRõ)m (CHz)~
(CRR )1_3 N'
R9
Id
The synthesis of compounds with the general structure I, particularly
compounds
according to formula Ie with the X' substituent beginning with a carbon atom
and X2
equal to -CONR9- can be accomplished according to scheme 2. Substituents R, R'
correspond to substituents as defined in detail in the claims.
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Scherne 2
R5 ,vkyl/f.{ II R5 AIkyUH
RLox 'Ha1duTMets R 4
Ra O 2lyw O
HO R7 a R\ O O R
Rs -- O R2' R 3 Re
1 b /C 3 d
o
\P_(CHR), (CHR)(CRp9,a O
\ I 6 x'
oi 4
Rs R5 Rs
Ra (CRR')i OH Ra (CRR')2 OH a (CRR'
R )3'4 OH
O O R7 O 1 O O I R7 O O ~ O
R~ ~/ RI O R
O R2 R3 Rs O RxJ\R3 Re O~ 3 Rs
R R -
7 8 9
R9 yiY -Rts
e HN~(CRIoRIi)m'(CH2)R y3-1'a
Rs Rs Y%Y' R1a
~-(CHa)~ \y3-Ya
Ra (CRR')ieN~(CR~oR~t)m
R~ ~O O R7 0
O R2p ~ a Rs Ie
R
Aldehyde or ketone phenols 1 are known or can be prepared by methods known in
the art. Compounds 1 can be transformed into aldehydes or ketones 3 by
reaction with
5 activated esters compounds 2 in the presence of a base like potassium or
cesium
carbonate in solvents like acetone, methyl-ethyl ketone, acetonitrile or N,N-
dimethylformamide in a temperature range between room temperature and 140 C.
In
case a specific ketone precursor 1 is not available, addition of the suitable
Grignard
reagent to a protected aldehyde compound 1, e. g. carrying a SEM protective
group (2-
10 trimethylsilanyl-ethoxymethyl) at the phenolic OH-function, followed by
oxidation of
the thus formed Grignard adduct, e. g. using m-chloro-perbenzoic acid, TEMPO
(2,2,6,6-tetramethyl-piperidine 1-oxyl) and tetrabutyl ammonium bromide in
dichlormethane preferably between 0 C and room temperature, and a standard
deprotection reaction yields then the desired keton compound 1. Aldehydes or
ketones 3
can be converted into acids 7, 8, or 9 by the following reaction sequences: i)
e. g. by
Wittig reaction with compounds 4 as reagents e. g. with potassium tert-
butoxide as base
in a solvent like tetrahydrofurane followed by mild acidic hydrolysis and
oxidation (e. g.
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sodium chlorite, sodium dihydrogenphosphate-dihydrate in tert-butanol / water
2:1 in
the presence of 2-methyl-2-butene at room temperature) (step b); ii) e. g. by
Horner
reaction with compounds 5 as reagents e. g. with sodium hydride as base in a
solvent like
tetrahydrofurane and subsequent hydrogenation and hydrolysis of the ester
function
(step c); iii) e. g. by Wittig reaction with acetals 6 as reagents e. g. with
potassium tert-
butoxide as base in a solvent like tetrahydrofurane and subsequent
hydrogenation of the
double bond, hydrolysis of the acetal function and oxidation to the acid e. g.
as described
above (step d). Acids 7, 8, or 9 can be chiral and can optionally be separated
into
optically pure antipodes by methods well known in the art, e. g.
chromatography on a
lo chiral HPLC column.
Condensation of acids 7, 8, or 9 with amines 10 can be performed using well
known procedures for amide formation, such as use of N-(3-dimethylaminopropyl)-
N'-
ethyl-carbodiimide-hydrochloride and optionally 4-dimethylamino-pyridine in
dichloromethane at temperatures between 0 C and room temperature yielding
compounds of formula le (step e). Those can optionally be hydrolyzed according
to
standard procedures, e. g. by treatment with an alkali hydroxide like LiOH or
NaOH in a
polar solvent mixture like tetrahydrofurane/ethanol/water to give carboxylic
acids Ie. In
case Rl is equal to tert-butyl, treatment with e. g. trifluoroacetic acid,
anisole in a solvent
like dichloromethane between room temperature and the reflux temperature of
the
solvents yields carboxylic acids Ie.
An analogous reaction scheme with the same reaction sequences applies for the
isomeric compound series leading to compounds of general formula I,
particularly
compounds according to formula If:
R5
4 Rs o ~.Y1s
/
I R5 or R7 ~ (CR,oRii)~.(CHZ) Ys.Ya
O ~ ~ (CRR'),,~ N=
O R R9 m
R ~O) R.
R2 XR3
If
The synthesis of compounds with the general structure I, particularly
compounds
according to formula Ig with Xl being an alkylene chain and X2 equal to NR9CO
can be
accomplished according to scheme 3. Substituents R, R' correspond to
substituents as
defined in detail in the claims.
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Scheme 3
0
R5 Alkyl/H RL'p)LXwiaoor rdaoio R5 Aikyl/H
p'ra'
R4 ~ O 2 or R4
~ Prot -Hai 3 R~~\ I
HO \ R' O R' O
RB a RB
R"=
X
or R" = Proi
JvL
/R" 4 RZ R3
R5
CRR')tuOH R4 (CRR') za
1I OH
R7 O O I 7 O
RuR
d 6 RS R5 R 5
4 (CRR')'NH 4 (CRR')~ R N
(CRR')3a
1 O O 7 ~ 9 O NH
~ 7 R9 O I e
RO R RO e R RI,,O R' R
R2 R3 R R' R3 R O Rz~ , ( ~ R a 9
Re
7 8
Q Y iy\ R13
e HO'k(CR10R71)(CH2)õys-1'a
m
R 5 O y2"Y rR73
O R4 (CRR71,
..N~(CR1oR11)m (CH2)o' 1\~~-Y
R\ O R7 R
R2 R3 Re Ig
Aldehyde or ketone phenols 1 are known or can be prepared by methods known in
the art. Compounds 1 can be transformed into aldehydes or ketones 4 by
reaction with
5 activated esters compounds 2 in the presence of a base like potassium or
cesium
carbonate in solvents like acetone, methyl-ethyl ketone, acetonitrile or N,N-
dimethylformamide in a temperature range between room temperature and 140 C.
Alternatively, a protective function can be attached to the phenolic hydroxy
group of
compounds 1, thus leading to compounds 4 with R" equal to a protective group
(step a).
io Depending on the synthetic route used, such a protective group can be
removed at a later
stage of the synthesis followed by attachment of activated esters compounds 2
as
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described above (see e. g. scheme 4). In case a specific ketone precursor 1 is
not available,
addition of the suitable Grignard reagent to a protected aldehyde compound 4,
e. g.
carrying a SEM (2-trimethylsilanyl-ethoxymethyl) protective group followed by
oxidation of the thus formed Grignard adduct, e. g. using m-chloro-perbenzoic
acid,
TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) and tetrabutyl ammonium bromide
in
dichlormethane preferably between 0 C and room temperature, yields then the
ketone
compound 4 carrying a protective function at the phenolic moiety.
Aldehydes or ketones 4 can be converted into primary or secondary amine
compounds 7 by oxime formation followed by reduction e. g. by catalytic
hydrogenation
io in the presence of a platinum catalyst (step b). Ketones 4 can be converted
into tertiary
amine compounds 7 e. g. by imine formation with p-methoxy-benzylamine,
addition of
an organolithium or organo magnesium reagent followed by deprotection of the p-
methoxy-benzylamine moiety with CAN (cerium (IV) ammonium nitrate). Conversion
of amine compounds 7 into amine compounds 7 carrying a R9 substituent
different from
hydrogen can by performed by e. g. attachment of a BOC-protective function to
the free
amino group. BOC protected amine compounds 7 can be alkylated at nitrogen
using
sodium hydride and a reactive alkyl halogenide/mesylate or triflate to give,
after standard
BOC-deprotection (TFA/CH2Cl2, or HCl in dioxane at 0 C to RT), compounds 7
carrying an R9 substituent different from hydrogen. Acids 5 or 6 can be
prepared from
suitably protected compounds 4 by reaction sequences as outlined for the
preparation of
acids 7, 8, and 9 in scheme 2 (step c). Acids 5 or 6 with R" being a e. g. a 2-
trimethylsilanyl-ethoxymethyl moiety can be converted into the aldehydes or
alkyl
ketones corresponding to compounds 4 with an optionally substituted alkylene
chain
between the aromatic moitety and the carbonyl function by standard Weinreb
synthesis:
i) Weinreb amide formation with methoxy-methylamine; ii) reaction with an
organolithium reagent or diisobultylaluminium hydride. Such aldehyde and keton
precursors can be converted into amino compounds 8 or 9 with an optionally
substituted
alkylene chain between the NHR9 moiety and the central aromatic unit by a
reaction
sequence similar to that described above for the conversion compounds 4 into
compounds 7 (step d). Amines 7, 8, or 9 can be chiral and can optionally be
separated
into optically pure antipodes by methods well known in the art, e. g.
chromatography on
a chiral HPLC column. Condensation of amines 7, 8, or 9 with acids 10 can be
performed
using well known procedures for amide formation, such as use of N-(3-
dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride and optionally 4-
dimethylamino-pyridine in dichloromethane at temperatures between 0 C and room
temperature yielding compounds Ig (step e). Those can optionally be hydrolyzed
according to standard procedures, e. g. by treatment with an alkali hydroxide
like LiOH
or NaOH in a polar solvent mixture like tetrahydrofurane/ ethanol/water to
give
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carboxylic acids of formula Ig. In case R' is equal to tert-butyl, treatment
with e. g.
trifluoroacetic acid, anisole in a solvent like dichloromethane between room
temperature
and the reflux temperature of the solvents yields carboxylic acids Ig.
An analogous reaction scheme with the same reaction sequences applies for the
isomeric compound series leading to compounds of general formula I,
particularly
compounds according to formula Ih:
R5
Rq R6 o Y2--Y~R13
= (CRR'),,...~ -(CH2)n YYe
R5 or R7 ~
O 7 R ~C]~tOR11}m
R
R i, Oi~( Rs
R2/ \R3
Ih
Scheme 4 describes the synthesis of intermediates with a tertiary carbon
center in
the alkylene chain between the central aromatic moiety and amide unit. These
1o intermediates have not yet been described in schemes 1, 2 or 3.
Acids 1, corresponding to compounds 5, or 6 (scheme 3) or compound 9 (scheme
2, but carrying a protective function instead of the oxyacetic acid head
group) can be
mono- and or dialkylated at the carbon alpha to the acid function using
standard enolate
alkylation chemistry either with the acid via a dianion formed with e. g. a
base like LDA
or lithium hexamethyldisilazide in solvents like tetrahydrofurane or 1,2-
dimethoxyethane, followed by addition of one or sequentially two different
alkyl halides,
a reaction preferably performed between -78 C and room temperature followed
by
hydrolysis; or as an option, such a reaction can be performed with the
corresponding
ester via a mono-anions; thus, acids 2 are obtained directly or of after ester
hydrolysis
(step a). Chiral acids 2 can be prepared with high enantiomeric purity by
using well
known methodologies of enantioselective alkylation reactions as e. g.
described in [Evans,
David A.; et al. Journal of Organic Chemistry (1990), 55(26), 6260-8]: acids
are converted
into enantiomerically pure N-acyl 1,3-oxazolidine-2-ones followed by
alkylation reaction
with e. g. sodium hexamethyldisilazide as base and alkyl iodides as alkylating
agents in
solvents like tetrahydrofurane at temperatures around -78 C and subsequent
hydrolysis.
In case, tertiary centers are formed, 0 alkylation might be predominant; thus,
C-
alkylated products can be formed from 0 alkylated products by reaction with
methyl-
aluminum-dichloride in a solvent like toluene at temperatures around -78 C as
described in [Suzuki, Tatsuo; et al. Tetrahedron Letters (2003), 44(18), 3713-
37161.
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Scheme 4
R6 R 5
R4 (CHZ)aa(CHR15) OH q (CHx)o.s(CR14RIOH
a II
R" O R~ 0 - R,
O I 0
~
R
RB Re
R" = Prot R" = Prot 0
or R" = O
~ 2 R' ~
b Fe R3
R5
R5
R4 (CH2)az(CRt4q~s'OH R4 (CHx)o-s(CR14R'~ OH
Rz~' RR3
O R~ ---- R X O ~
e ~ ' R
R R" = Prot 0 Re
3 4
a
R (CH2)o-2(CRuR1s) 4 R5 (CHz)a2(CRuR15)(CH2)
O Rz 3R R2 3R I
R~~ O qe H~ RO \ R7 Hr
d O RB e O Re
6
f t
R5 Rs R5 Re
R4 (CHz)o-z(CR'4R1') I R4 (CH2)0.i(CR14Rt5)(CH2)
R2 R3 / I -,/NH qZ R3
R1.1O ~O q7 R1,1O ~O R' ~/
O qe O qg
7 8
R6
q (CHz)o-z(CRt4qt5)(CHa)jO
Rz R3
6 9 R~0 \ I ~ OH
0 Ra
9
Acids 2 can be transformed into acids 2 with an alkoxyacetic acid head group
and
be used in amide forming reactions as described in schemes 1, 2 and 3 e. g.
by: i) ester
5 formation; ii) deprotection; iii) condensation with alpha halo tert-butyl
esters as
described in scheme 1; iv) selective ester hydrolysis. Alternativeley, acids 2
can be reduced
to the primary alcolhol e. g. using borane/tetrahydrofurane as reagent (step
b).
Deprotection followed by condensation with alpha halo esters as described in
scheme 1
gives then compounds 4 (step c).
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Oxidation of compounds 4 e. g. using Swern conditions (oxalyl chloride /
dimethylsulfoxide / triethylamine in dichloromethane, -78 C to room
temperature)
gives compounds 5 (step d). Compounds 5 can optionally be elongated by one
carbon by
Wittig reaction using e.g. compound 4 (scheme 2) as reagent e. g. with
potassium tert-
butoxide as base in a solvent like tetrahydrofurane followed by mild acidic
hydrolysis
(step e). Optionally, this elongation procedure can be repeated with compounds
6 in
order to introduce a second (CH2) moiety. Aldehydes 5 and 6 can be converted
into
amino compounds 7 and 8 in analogy to the conversion described for compound 4
into
compound 7 in scheme 3. Alternatively, compounds 6 or compounds 6 containing
an
io additional (CH2) group can be oxidized to the corresponding acids 9 e. g.
using sodium
chlorite, sodium dihydrogenphosphate-dihydrate in tert-butanol / water 2:1 in
the
presence of 2-methyl-2-butene at room temperature (step g). Amines 7 and 8,
acids 2
with an alkoxyacetic acid head group and acids 9 can be chiral and can
optionally be
separated into optically pure antipodes by methods well known in the art, e.
g.
chromatography on a chiral HPLC column.
Amines 7 and 8 as well as acids 9 can be used in amide forming reactions as
described in schemes 1, 2 and 3.
Scheme 5 to scheme 8 describe the synthesis of synthons 10 and 11 (scheme 1),
of
synthon 10 (scheme 2) and of synthon 10 (scheme 3).
Scheme 5
R O NHM82+CI
R 13~ O+ NMe2.HCI + paraformaldehyde a 13
1 2 O
:I120b 3
R1z 0 R12' 0
I ~ OH c O~Alkyl
R13 N R12 R
5 4
Pyridines 5 can be synthesized in a three step synthesis from ketones 1(scheme
5).
A mixture of ketones 1 with paraformaldehyde and dimethylamine hydrochloride
in a
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solvent like ethanol in the presence of an acid like 37% HCl is heated to
reflux for 2 to 10
hours to give aminoketones 2 (step a). Reaction of compounds 2 with 3-
aminocrotonic
acid esters 3 in acetic acid at reflux for 2 to 8 hours gives esters 4 (step
b), which can be
hydrolyzed (alkali hydroxide in solvents like THF, dioxane or DMSO) to give
acids 5
(step c). Pyridines 4 can alternatively be synthesized following procedures
described in
[Al-Saleh, Balkis; Abdelkhalik, Mervat Mohammed; Eltoukhy, Afaf Mohammed;
Elnagdi,
Mohammed Hilmy. Enaminones in heterocyclic synthesis: A new regioselective
synthesis
of 2,3,6-trisubstituted pyridines, 6-substituted-3-aroylpyridines and 1,3,5-
triaroylbenzenes. Journal of Heterocyclic Chemistry (2002), 39(5), 1035-1038].
1o Disubstituted pyridines 4 can be prepared according to procedures described
in
[Katsuyama, Isamu; Ogawa, Seiya; Yamaguchi, Yoshihiro; Funabiki, Kazumasa;
Matsui,
Masaki; Muramatsu, Hiroshige; Shibata, Katsuyoshi. A convenient and
regioselective
synthesis of 4-(trifluoromethyl)pyridines. Synthesis (1997), (11), 1321-13241.
Scheme 6
O 0
R12 R12
O O-alkyl b
2
O-a{kyl R1r
R12" -alkyl c N- O
13
\
O O NH N O-alkyl
R12 R13~j CIH R12
0-alkyl \NH2
3 4 5
O O a
R12
d
R12'
N-. O
R13
N OH
R12
6
The synthesis of pyrimidine acids 6 is described in scheme 6. Reaction of 3-
oxo-
esters 1 with triethyl orthoformate in acetic anhydride at room temperature to
reflux for
1 to 8 hours gives an E/Z mixture of the 3-ethoxy-acrylic acid esters 3 (step
a). Diketo-
esters 2 are reacted with methyl triflate in the presence of cesium carbonate
in acetonitrile
to give 0-methylated products 3 (step b) [S. W. McCombie et al., Bioorganic &
Medicinal Chemistry Letters 13 (2003), 567-571], thus yielding substituted
enolethers 3
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(R12'not H). Reaction with amidine hydrochlorides 4 in ethanol in the presence
of alkali
tert-butoxide at room temperature gives access to esters 5 (step c). Esters 5
can be
hydrolyzed (alkali hydroxide in solvents like THF) dioxane or DMSO) to give
acids 6
(step d).
Scheme 7
O O
OH Y! O-al IM a- Y4/ O-alkyi
R13/B. OH + ~)/ ~ Y2
/ 1%~ 13~ 1.~
Ha! Y R Y
2 3
H
V4/Y!NRs
,Y
d /' 2 b
Hal a
6
O
H
Y\ N~R9 c ~'/~ OH
4 2
13 1 R13 Y1:
R Y
5 4
A general synthesis for acids 4 and amines 5 is depicted in scheme 7. Suzuki-
coupling with boronic acides 1 and 4-halo-benzoic acid derivatives 2, 6-halo-
pyridazine-
3-carboxylic acid derivatives 2, 5-halo-pyrazine-2-carboxylic acid derivatives
2, 6-halo-
io nicotinic acid derivatives 2, 5-halo-pyridine-2-carboxylic acid derivatives
2, 2-halo-
pyrimidine-5-carboxylic acid derivatives 2 or 5-halo-pyrimidine-2-carboxylic
acid
derivatives 2 or the corresponding optionally substituted halo-anilino
compounds 6 with
Pd(PhP)4 or PdC12(dppf) [(1,1'-bis(diphenylphosphino)ferrocene)-
dichloropalladium
(II) x CH2CI2 (1:1)) in toluene, dimethoxyethane, ethanol or DMF in the
presence of
cesium carbonate, potassium carbonate or cesium fluoride at room temperature
to 90 C
for 2 to 8 h gives esters 3, acids 4 or anilines 5 (step a, d). Esters or
acids 2 are either
commercially available or can be prepared by methods known to a person skilled
in the
art. Esters 3 can be hydrolyzed (alkali hydroxide in solvents like THF,
dioxane or DMSO)
to give acids 4 (step b). A Curtius rearrangement can be used to transform
acids 4 into
the analogous BOC-protected anilines: first, the acid chlorides are
synthesized with e. g.
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oxalyl chloride/DMF in dichioromethane. Then, reaction with sodium azide in
DMF/
dichloromethane followed by heating to reflux in the presence of 2-methyl-2-
propanol
gives the BOC protected anilines. Alternatively, such BOC protected anilines
can be
obtained from acids 4 in a one pot procedure by treatment with
diphenylphosphoryl
azide in 2-methyl-2-propanol in the presence of triethylamine and anhydrous 4-
toluene
sulfonic acid at temperatuares arount 100 C. Alkylation of these BOC
protected anilines
with an R9-halide in the presence of sodium hydride in solvents like DMF
followed by
BOC-deprotection with TFA or HCl in dioxane yields anilines 5 (step c).
Scheme 8
Y4I ~~''1 I OH a - yi i ~CI b ~,a~~~
~ I~ \~N
Y2 jl
R Y R1a Yt= Ris~~Yt;Y
2 3
9 e c
Y4 ~~ O
N\R 9
:YZ R10'~ly R~i y4 ~00 Yai~
y n OH
R13~Y> 1;Y R I
R Y R13Y~ =
$ 6 4
f d k
0
Rt6
Y~h Y4~~~I~~~ /OH 3
Ya~ ~ n ON
2 10 Rtt
tyl-' Y R10,R11 E II Y2 Rlo R11 iI Y R
R's//R~,I . R's/'YI
7, R16 = leaving group 6 9
Alcohols 1 in scheme 8 comprising a chain length n equal to one [obtained by
reduction of esters 3 (scheme 7) e. g. using diisobutylaluminium hydride-
solution (in
toluene) at -30 C to room temperature for 30 min to 3 h in solvents like THF]
can be
converted into analogues with a chain length of n+1 carbon atoms by methods
well
known in the art, e. g. by conversion of the primary alcohol into a suitable
leaving group,
e. g. a halide (2, step a), followed by reaction with cyanide to form nitriles
3 (step b) and
saponification to acids 4 (step c). Acids 4 can be further transformed into
the primary
alcohols 5(R10 = H, Rl i= H), e. g. by using diborane in tetrahydrofurane
(step d).
Optionally, such alcohols 5 can be elongated to a chain length of n+1 carbon
atoms by
repeating the synthesis described for alcohols 1 to 5. In order to introduce
substituents
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R10 and/or R" different from hydrogen, cyano intermediates 3 can be reacted
with alkyl
Grignard reagents Rl MgX in solvents like ether or tetrahydrofurane between 0
C and
then reflux temperature of the solvent to form the corresponding R10CO-alkyl
ketones 6
(step e) or with diisobutylaluminium hydride the corresponding aldehydes
6(R10=H).
Treatment of compounds 6 with an alkyllithium reagent R11Li in solvents like
ether or
tetrahydrofurane gives alcohols 5 (step f); treatment of compounds 6 with
lithium
aluminium hydride in solvents like tetrahydrofurane or ether or with sodium
borohydride in solvents like ethanol or methanol, preferably at temperatures
between -
C and 40 C, gives alcohols 5 with R11=H (step f). The alcohol compounds 5
which
1o contain a chiral center can optionally be separated into optically pure
antipodes by
methods well known in the art, e. g. chromatography on a chiral HPLC column,
or by
derivatization with an optically pure acid to form esters, which can be
separated by
conventional HPLC chromatography and can then be converted back to the
enantiomerically pure alcohols 5. The reduction of ketones 6 to the
corresponding
15 secondary alcohols 5 of scheme 8 can also be carried out in an
enantioselective fashion
leading to the (R)- or (S)-alcohols 5, e. g. by treatment with borane-
dimethylsulfide
complex and (S)- or (R)-2-methyl-CBS-oxazaborolidine as chiral catalyst in
tetrahydrofurane, preferably at temperatures between -78 C and ambient
temperature,
according to Corey et al. (E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem.
Soc. 1987,
109, 5551-5553), or by treatment with (+)- or (-)-B-chlorodiisopinocampheyl-
borane
(DIP-Cl), according to Brown et al. (P. V. Ramachandran, B. Gong, A. V.
Teodorovic, H.
C. Brown, Tetrahedron: Asymmetry 1994, 5, 1061-1074). Aldehydes 6(R10= H, n =
0) can
also be synthesized from primary alcohols 1 by methods known in the art, e. g.
by
treatment with pyridinium chlorochromate in dichloromethane, preferably at
temperatures between room temperature and the reflux temperature of
dichloromethane, or by treatment with manganese dioxide in solvents like
dichloromethane, preferably at room temperature (step g). These aldehydes 6
can be
converted to the corresponding secondary alcohols 5 through reaction with
alkyl
organometallic compounds, preferably under the conditions discussed above.
Finally, the
3o alcohols 5 of scheme 8 can be converted into compounds of formula 7, e. g
by treatment
with methanesulfonyl chloride in dichloromethane in the presence of a base
like
triethylamine preferably in a temperature range between -20 C and room
temperature
or thionyl chloride in dichloromethane at 0 C to room temperature or by
reaction with
carbon tetrachloride or carbon tetrabromide and triphenylphosphine in solvents
like
tetrahydrofurane preferably in a temperature range between room temperature
and the
reflux temperature of the solvents or by treatment with triflic anhydride, 2,6-
lutidine and
4-dimethylaminopyridine in dichloromethane between -30 C and room
temperature;
thus yielding compounds of formula 7 as methane-sulfonates, triflates,
chlorides or
bromides, respectively (step h). Compounds of formula 7 can further be
converted
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(reaction step i) to the amines 8 in solvents like DMA, DMF or dichloromethane
at room
temperature with an excess of the corresponding amine.
Alpha mono- or di-substituted acids 9(R10 and/or R" not H) can be synthesized
via esters of compounds 4, by treatment with a base like LDA (lithium
diisopropylamide)
or lithium hexamethyldisilazide in solvents like tetrahydrofurane or 1,2-
dimethoxyethane, followed by addition of one or sequentially two different
alkyl halides,
a reaction preferably performed between -78 C and room temperature followed
by
hydrolysis to acid 9 (step k). Compounds 9 can be chiral and can optionally be
separated
into optically pure antipodes by methods well known in the art, e. g.
chromatography on
1o a chiral HPLC column, or by derivatization with an optically pure acid to
form esters,
which can be separated by conventional HPLC chromatography and then converted
back
to the enantiomerically pure alcohol. Additionally, the asymmetric alkylation
can be
done with chiral amides of 4 which are well known to a person skilled in the
art.
Compounds of the general formula I can contain one or more stereocenters and
can optionally be separated into optically pure enantiomers or diastereomers
by methods
well known in the art, e. g. by HPLC chromatography, chromatography on a
chiral HPLC
column, chromatography with a chiral eluant or by derivatization with an
optically pure
alcohol to form esters, which can be separated by conventional HPLC
chromatography
and then converted back to the enantiomerically pure acids I(R1= H). In
addition,
2o racemic compounds can be separated into their antipodes via diastereomeric
salts by
crystallization with optically pure amines such as e. g. (R) or (S)-1-phenyl-
ethylarnine,
(R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or quinidine.
The following tests were carried out in order to determine the activity of the
compounds of formula (I).
Background information on the performed assays can be found in: Nichols JS et
al.
"Development of a scintillation proximity assay for peroxisome proliferator-
activated
receptor gamma ligand binding domain", (1998) Anal. Biochem. 257: 112-119.
Full-length cDNA clones for humans PPARS and PPARa and mouse PPARy were
obtained by RT-PCR from human adipose and mouse liver cRNA, respectively,
cloned
3o into plasmid vectors and verified by DNA sequencing. Bacterial and
mammalian
expression vectors were constructed to produce glutathione-s-transferase (GST)
and
Gal4 DNA binding domain proteins fused to the ligand binding domains (LBD) of
PPAR5 (aa 139 to 442), PPARy (aa 174 to 476) and PPARa (aa 167 to 469). To
accomplish this, the portions of the cloned sequences encoding the LBDs were
amplified
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38 -
from the full-length clones by PCR and then subcloned into the plasmid
vectors. Final
clones were verified by DNA sequence analysis.
Induction, expression, and purification of GST-LBD fusion proteins were
performed in E. coli strain BL21(pLysS) cells by standard methods (Ref Current
Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al.).
Radioligand Bindin Assay
PPAR8 receptor binding was assayed in HNM10 (50mM Hepes, pH 7.4, 10 mM
NaCI, 5mM MgC12, 0.15 mg/ml fatty acid-free BSA and 15 mM DTT). For each 96
well
reaction a 500 ng equivalent of GST-PPARS-LBD fusion protein and radioligand,
e.g.
lo 20000 dpm {2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl-
ditritiomethylsulfanyl]-phenoxy}-acetic acid, was bound to 10 g SPA beads
(PharmaciaAmersham) in a final volume of 50 l by shaking. The resulting
slurry was
incubated for lh at RT and centrifuged for 2 min at 1300g. The supernatant
containing
unbound protein was removed and the semidry pellet containing the receptor-
coated
beads was resuspended in 50 l of HNM. Radioligand was added and the reaction
incubated at RT for lh and scintillation proximity counting performed in the
presence of
test compounds was determined. All binding assays were performed in 96 well
plates and
the amount of bound ligand was measured on a Packard TopCount using OptiPlates
(Packard). Dose response curves were done in triplicates within a range of
concentration
from 10-10 M to 10-4 M.
PPARa receptor binding was assayed in TKE50 (50mM Tris-HC1, pH 8, 50 mM
KC1, 2mM EDTA, 0.1 mg/ml fatty acid-free BSA and 10 mM DTT). For each 96 well
reaction an 140 ng equivalent of GST-PPARoc-LBD fusion protein was bound to 10
g
SPA beads (PharmaciaAmersham) in a final volume of 50 l by shaking. The
resulting
slurry was incubated for lh at RT and centrifuged for 2 min at 1300g. The
supernatant
containing unbound protein was removed and the semidry pellet containing the
receptor-coated beads was resolved in 50 l of TKE. For radioligand binding
e.g. 10000
dpm of 2(S)-(2-benzoyl-phenylamino)-3-{4- [ 1,1-ditritio-2-(5-methyl-2-phenyl-
oxazol-
4-yl)-ethoxy]-phenyl}-propionic acid or 2,3-ditritio-2(S)-methoxy-3-{4-[2-(5-
methyl-2-
phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid in 50 ul
were
added, the reaction incubated at RT for lh and scintillation proximity
counting
performed. All binding assays were performed in 96 well plates and the amount
of bound
ligand measured on a Packard TopCount using OptiPlates (Packard). Nonspecific
binding was determined in the presence of 10-4 M unlabelled compound. Dose
response
curves were done in triplicates within a range of concentration from 10-10 M
to 10"4 M.
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PPARy receptor binding was assayed in TKE50 (50mM Tris-HCI, pH 8, 50 mM
KCI, 2mM EDTA, 0.1 mg/ml fatty acid-free BSA and 10 mM DTT). For each 96 well
reaction an 140 ng equivalent of GST-PPARy-LBD fusion protein was bound to 10
g
SPA beads (PharmaciaAmersham) in a final volume of 50 ul by shaking. The
resulting
slurry was incubated for lh at RT and centrifuged for 2 min at 1300g. The
supernatant
containing unbound protein was removed and the semidry pellet containing the
receptor-coated beads was resolved in 50 ul of TKE. For radioligand binding
e.g. 10000
dpm 2(S)-(2-benzoyl-phenylarnino)-3-{4-[l,l-ditritio-2-(5-methyl-2-phenyl-
oxazol-4-
yl)-ethoxy]-phenyl}-propionic acid in 50 l were added, the reaction incubated
at RT for
1o lh and scintillation proximity counting performed. All binding assays were
performed in
96 well plates and the amount of bound ligand measured on a Packard TopCount
using
OptiPlates (Packard). Nonspecific binding was determined in the presence of 10-
4 M
unlabelled compound. Dose response curves were done in triplicates within a
range of
concentration from 10-10 M to 10"4 M.
Luciferase Transcriptional Reporter Gene Assays
Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium
containing 10% FBS at 37 C in a 95 fo02:5%CO2 atmosphere. Cells were seeded
in 6 well
plates at a density of 105 Cells/well and then batch-transfected with either
the pFA-
PPARS-LBD, pFA-PPARy-LBD or pFA-PPARa-LBD expression plasmids plus a reporter
plasmid. Transfection was accomplished with the Fugene 6 reagent (Roche
Molecular
Biochemicals) according to the suggested protocol. Six hours following
transfection, the
cells were harvested by trypsinization and seeded in 96 well plates at a
density of 104
cells/well. After 24 hours to allow attachment of cells, the medium was
removed and
replaced with 100 ul of phenol red-free medium containing the test substances
or control
ligands (final DMSO concentration: 0:1%). Following incubation of the cells
for 24 hours
with substances, 50 l of the supernatant was discarded and then 50 l of
Luciferase
Constant-Light Reagent (Roche Molecular Biochemicals) to lyse the cells and
initiate the
luciferase reaction was added. Luminescence for luciferase was measured in a
Packard
TopCount. Transcriptional activation in the presence of a test substance was
expressed as
fold-activation over cells incubated in the absence of the substance. EC50
values were
calculated using the XLfit program (ID Business Solutions Ltd. UK).
The free acids of the compounds of the present invention (Rl is hydrogen)
exhibit
TC50 values of 0.5 nM to 10 M, preferably 1 nM to 100 nM for PPARat and/or
IC50
values of 1 nM to 10 M, preferably 10 nM to 5 M for PPARS and/or IC50 values
of
100 nM to 10 [tM, preferably 500 nM to 5 M for PPARy. Compounds, in which R'
is
not hydrogen are converted in vivo to compounds in which R' is hydrogen. The
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following table shows measured values for selected compounds of the present
invention.
PPARa PPARy PP.ARS
IC50 ( mol/1) IC50 ( mol/l) IC50 ( mol/1)
Example 09 0.42 >10 0.58
Example 16 0.008 >10 >10
Example 20 0.024 1.08 0.94
The compounds of formula (I) and their pharmaceutically acceptable salts and
esters can be used as medicaments, e.g. in the form of pharmaceutical
preparations for
enteral, parenteral or topical administration. They can be administered, for
example,
perorally, e.g. in the form of tablets, coated tablets, drageees, hard and
soft gelatine
capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of
suppositories,
parenterally, e.g. in the form of injection solutions or infusion solutions,
or topically, e.g.
in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner
which will be familiar to any person skilled in the art by bringing the
described
compounds of formula (I) and their pharmaceutically acceptable, into a
galenical
administration form together with suitable, non-toxic, inert, therapeutically
compatible
solid or liquid carrier materials and, if desired, usual pharmaceutical
adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also
organic
carrier materials. Thus, for example, lactose, corn starch or derivatives
thereof, talc,
stearic acid or its salts can be used as carrier materials for tablets, coated
tablets, dragees
and hard gelatine capsules. Suitable carrier materials for soft gelatine
capsules are, for
example, vegetable oils, waxes, fats and semi-solid and liquid polyols
(depending on the
2o nature of the active ingredient no carriers are, however, required in the
case of soft
gelatine capsules). Suitable carrier materials for the production of solutions
and syrups
are, for example, water, polyols, sucrose, invert sugar and the like. Suitable
carrier
materials for injection solutions are, for example, water, alcohols, polyols,
glycerol and
vegetable oils. Suitable carrier materials for suppositories are, for example,
natural or
hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier
materials for
topical preparations are glycerides, semi-synthetic and synthetic glycerides,
hydrogenated
oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols,
polyethylene glycols and
cellulose derivatives.
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Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-
improving agents, flavour-improving agents, salts for varying the osmotic
pressure,
buffer substances, solubilizers, colorants and masking agents and antioxidants
come into
consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula (I) can vary within wide limits
depending
on the disease to be controlled, the age and the individual condition of the
patient and
the mode of administration, and will, of course, be fitted to the individual
requirements
in each particular case. For adult patients a daily dosage of about 0.1 mg to
about
1000 mg, especially about 1 mg to about 100 mg, comes into consideration.
Depending
io on the dosage it is convenient to administer the daily dosage in several
dosage units.
The pharmaceutical preparations conveniently contain about 0.1-500 mg,
preferably 0.5-100 mg, of a compound of formula (I).
The following examples serve to illustrate the present invention in more
detail.
They are, however, not intended to limit its scope in any manner.
Examples
Abbreviations:
AcOEt = ethyl acetate, n-BuLi = n-butyllithium, DBU = 1,8-
diazabicyclo[5.4.0]undec-7-
ene, MeC12 = dichloromethane; DEAD = diethyl azodicarboxylate, DIAD =
diisopropyl
azodicarboxylate, DIBAL-H solution = diisobutylaluminum hydride solution, DMF
=
2o N,N-dimethylformamide, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone, eq. = equivalents, h hour(s), DMSO = dimethyl sulfoxide, HPLC =
high
performance liquid chromatography, i. V. = in vacuo, LDA = lithium
diisopropylamide,
PdC12(dppf) = (1,1'-bis(diphenylphosphino)ferrocene)dichloro-
palladiurn(II).CHZC12
(1:1), Pd(Ph3P)4 = tetrakis(triphenylphosphine)palladium, POC13 = phosphorus
oxychloride, RT = room temperature, TFA = trifluoroacetic acid, TFAA =
trifluoroacetic
anhydride, THF = tetrahydrofurane.
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Examnle 1
[rac] -2- [4-(1-{ [4-Cyclopropyl-2- (4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid
A] [racl-2-(4-(1-1 f4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbon~Ll]=
aminol-ethyl)-2-methyl-phenoxyl-2methyl-propionic acid ethyl ester
0.25 g (0.94 mmol) of [rac]-2-[4-(1-amino-ethyl)-2-methyl-phenoxy]-2-methyl-
propionic acid ethyl ester [PCT Int. Appl.(2002), 35 pp. WO 2002096894A1] and
0.29 g
(1.00 mmol) of 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic
acid (example 1E] ) were dissolved in 10 ml of CHaCl2. To this solution were
added 0.22 g
lo (1.13 mmol) of N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide-
hydrochloride and
0.15 g (1.22 mmol) of N,N-dimethylaminopyridine and this mixture was stirred
for 20
hours at RT. The solvent was removed by evaporation and the crude product was
purified by chromatography (Si02; n-heptane / AcOEt = 4:1 to 1:1) to give 0.42
g of the
title compound as a colorless foam.
MS: 556.2 (M+H)+.
B1 f racl -2- (4-( I-{ [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-
5-carbonyll -
amino}-ethyl)-2-methyl-phenoxyl-2-methyl-propionic acid
0.40 g (0.72 mmol) of the above prepared jrac]-2-[4-(1-{[4-cyclopropyl-2-(4-
trifluoromethyl-phenyl) -pyrimidine-5-carbonyl] -amino } -ethyl)-2-methyl-
phenoxy] -2-
methyl-propionic acid ethyl ester was dissolved in 7.5 ml of THF / MeOH = 2:1.
To the
stirred solution was added 2.16 ml (2.16 mmol) of a LiOH-solution (IM in
water). After
16 hours, the reaction mixture was poured into crashed ice / HCl and extracted
twice
with CH2C12; the organic layers were washed with water, dried over magnesium
sulfate,
filtered and evaporated to give 0.40 g of crude product. Recrystallization
from AcOEt / n-
heptane gave 0.30 g of pure title compound as colorless solid.
MS: 528.4 (M+H)+.
The 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
used in
IA] was synthesized as follows:
Cl (E,Z)-2-Cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester
3o A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl
ester and of
23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was
refluxed
at 150 C for 5h. The reaction mixture was concentrated at 95 C under reduced
pressure
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to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid
methyl
ester.
MS: 199.3 (M+H)+.
D14-Cvclonropyl-2-(4-trifluoromethXl-phenyl)-pyrimidine-5-carboxylic acid
ethvl ester
To a solution of 4.74 g (18.19 mmol) 4-trifluoromethyl-benzamidine HC1 in 50
ml of
ethanol was added 1.818 g (18.186 mmol) of sodium tert-butoxide. After 2 min,
3.605 g
of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester was
added and
the reaction mixture was then stirred over night at RT. The ethanol was
removed under
reduced pressure, the residue taken up in ether and washed with 1N HCI and
water. The
1o ether solution was concentrated under reduced pressure and the crude
product purified
by chromatography over silica gel with AcOEt/heptane 1:3 to give 4.25 g of
pure 4-
cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl
ester.
MS: 337.1 (M+H)+.
El 4-Cy-clopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
The solutions of 3.6 g (10.7 mmol) of 4-cyclopropyl-2-(4-trifluoromethyl-
phenyl)-
pyrimidine-5-carboxylic acid ethyl ester in 40 ml of ethanol and of 1.07 g
(26.7 mmol) of
sodium hydroxide in 5 ml of H20 were mixed and then refluxed for 1 hour. After
cooling
to ambient temperature, 6.7 ml of 4N aqueous hydrochloric acid was added. The
reaction
mixture was extracted with three portions of ethyl acetate. The combined
organic phases
were washed with water and brine and dried over anhydrous sodium sulfate. The
4-
cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
crystallized
upon concentrating the solution by evaporation. After cooling in an ice bath,
3.08 g of
white crystals were obtained.
MS: 307.2 (M-H)".
Example 2
[rac]-2-[4-(1-{ [4-Cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid
A] In analogy to the procedures described in example 1A] and 113], [rac]-2-[4-
(1-amino-
ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester [PCT Int.
Appl.(2002), 35
3o pp. WO 2002096894A1] was reacted with 4-cyclopropyl-2-(3-trifluoromethyl-
phenyl)-
pyrimidine-5-carboxylic acid (example 2C]) to give [rac]-2-[4-(1-{[4-
cyclopropyl-2-(3-
trifluoromethyl-phenyl)-pyrimidine-5-carbonyl] -amino}-ethyl) -2-methyl-
phenoxy] -2-
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methyl-propionic acid ethyl ester, which was subsequently saponified to yield
the title
compound as colorless solid.
MS: 528.4 (M+H)+.
The 4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimid'uxe-5-carboxylic acid
used in
2A] was synthesized as follows:
Bl 4-CXclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
ethyl ester
To a solution of 0.953 g (4.24 mmol) commercially available 3-trifluoromethyl-
benzamidine hydrochloride in 10 ml of ethanol was added 0.408 g (4.25 mmol) of
sodium tert-butoxide. Two min. later, 0.901 g (4.25 mmol) of crude (E,Z)-2-
lo cyclopropane-carbonyl-3-ethoxy-acrylic acid methyl ester (example 1C],
containing
some Et-ester) was added and the reaction allowed to proceed over night at RT.
The
mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase
extracted
again with AcOEt, the combined organic layers were washed with water, dried
over
sodium sulfate, and evaporated to dryness. Flash chromatography (Si02,
hexane/AcOEt=
9/1) yielded finally 1.253 g of title compound as white waxy solid (mixture of
Me/Et-
ester).
MS: 322.1, 336.0 (M)t.
Cl 4-Cycloprouyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
In analogy to the procedure described in examples IE], 4-cyclopropyl-2-(3-
trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester was
saponified to yield
the title compound as colorless solid.
MS: 307.2 (M-H)-.
Example 3
[rac]-2-Methyl-2-(2-methyl-4-{ 1- [(3'-trifluoromethyl-biphenyl-4-carbonyl)-
aminol-
ethyl}-phenoxy)-propionic acid
A] In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-
(1-amino-
ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester [PCT Int.
Appl.(2002), 35
pp. WO 2002096894A1] was reacted with 3'-trifluoromethyl-biphenyl-4-carboxylic
acid
(example 3B]) to give [rac]-2-methyl-2-(2-methyl-4-{1-[(3'-trifluoromethyl-
biphenyl-4-
3o carbonyl)-amino]-ethyl}-phenoxy)-propionic acid ethyl ester, which was
subsequently
saponified to yield the title compound as colorless solid.
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-45-
MS: 484.4 (M-H)-.
The 3'-trifluoromethyl-biphenyl-4-carboxylic acid used in 3A] was synthesized
as
follows:
B 1 3'-Trifluoromethyl-biphenyl-4-carboxylic acid
3.0 g (12.1 mmol) of 4-iodo benzoic acid was dissolved in 40 ml of 1,2-
dimethoxy-
ethane, 20 ml of water was added, followed by 2.44 g (12.5 mmol) of 3-
(trifluoromethyl)-
benzeneboronic acid, 2.27 g (20.8 mmol) of sodium carbonate and 0.28 g (0.24
mmol) of
tetrakis(triphenylphosphine)palladium. This mixture was stirred for 2 hours at
95 C,
cooled down to RT and filtered. The pH of this solution was adjusted with HCl
(1N) to
1o pH 1-2, and it was then extracted twice with AcOEt. The organic layers were
washed with
water, dried over magnesium sulfate, filtered and evaporated to give 3.58 g
crude
product, which was purified by chromatography over silica gel with a gradient
of MeC12
and MeOH to give 2.70 g of the title compound as light yellow solid.
MS: 265.0 (M-H)-.
Example 4
[rac] -2-Methyl-2- (2-methyl-4- { 1- [ (4'-trifluoromethyl-biphenyl-4-
carbonyl)-arninoJ -
ethyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
amino-
ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester [PCT Int.
Appl.(2002), 35
pp. WO 2002096894A1] was reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic
acid
(prepared in analogy to the procedure described in example 3B] ) to give [rac]
-2-methyl-
2-(2-methyl-4-{ 1-[ (4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-ethyl}-
phenoxy)-
propionic acid ethyl ester, which was subsequently saponified to yield the
title compound
as colorless solid.
MS: 484.3 (M-H)-.
Example 5
[rac]-2-Methyl-2-(2-methyl-4-{1- [2-methyl-6-(4-trifluoromethyl-phenyl)-
pyridin-3-
ylcarbamoyl]-ethoxy}-phenoxy)-propionic acid
A] In analogy to the procedures described in example 1A] and 1B], [rac)-2-[4-
(1-
carboxy-ethoxy)-2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester
(example 5G] )
was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine
(example
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5E}) to give [rac]-2-methyl-2-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-
phenyl)-
pyridin-3-ylcarbamoyl]-ethoxy}-phenoxy)-propionic acid ethyl ester, which was
subsequently saponified to yield the title compound as colorless solid.
MS: 515.2 (M-H)-.
The necessary building block 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylarnine
used in the procedure above was prepared as follows:
B] 3-Dimethylamino-1-(4-trifluoromethyl-phenyl)-propan-l-one hydrochloride
4-(Trifluoromethyl) acetophenone (4.97 g, 26.4 mmol), paraformaldehyde (1.586
g, 2
eq.) and dimethylamine hydrochloride (3.231 g, 1.5 eq.) were mixed together in
7 ml of
lo EtOH, treated with 0.08 ml of 37% HC1, and heated to reflux for 5h. Cooling
down to
ambient temperature, filtration and washing with tiny amounts of cold EtOH
delivered
4.59 g of the title compound as white crystals, mp. 128-42 C (dec.).
MS: 246.3 (M+H)+.
Cl 2-Methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester
4.59 g (16.3 mmol) of the above prepared 3-dimethylamino-1-(4-trifluoromethyl-
phenyl)-propan-l-one hydrochloride and 1.86 g (1.0 eq.) of 3-aminocrotonic
acid
methyl ester were dissolved in 50 ml of AcOH and heated to reflux for 4h.
After cooling,
the bulk of the solvent was evaporated i. V., the residue dissolved in AcOEt,
and washed
with water and brine. Drying over sodium sulfate, evaporation of the solvents
and flash
chromatography (SiO2, hexane/AcOEt=8/2) delivered finally 2.40 g of the title
compound as light yellow waxy solid.
MS: 296.1(M+H){.
Dl [2-Methyl-644-trifluoromethyl-phenyl)-pyridin-3-yl1 -carbamic acid tert-
butyl ester
4.30 g (15.3 mmol) of 2-methyl-6-(4-trifluoromethyl-phenyl) -nicotinic acid
(prepared
from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester in
analogy to the
procedure described in example lE]) was dissolved in 85 ml of 2-methyl-2-
propanol and
3.18 ml = 2.32 g (22.9 mmol) of triethylamine was added. After 5 min., 4.97 ml
= 6.64 g
(22.9 mmol) of diphenylphosphoryl azide (95%) was added. The reaction mixture
was
then stirred at reflux (oil bath 100 C). After 10 min., 0.53 g (3.1 mmol) of
anhydrous 4-
3o toluene sulfonic acid was added and stirring continued for 1 hour at
reflux. The solvent
was then completely removed by evaporation at high vacuum; the residue was
dissolved
in Et20 and washed with HZO,1N HCI, and NaHCO3 solution. The combined organic
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phases were dried over anhydrous magnesium sulfate and evaporated. The crude
product
was purified by crystallization (EtOAc, n-heptane) to give 4.05 g of the title
compound as
colorless solid.
MS: 353.3 (M+H)+.
El2-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3- lamine
To a solution of 2.0 g (5.68 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-
pyridin-3-
yl]-carbarnic acid tert-butyl ester in 25 ml of MeCla were added (drop by
drop) 2.17 ml
(28.4 mmol) of trifluoroacetic acid at RT. After 20 hours, the solvent was
removed by
evaporation in vacuo, the residue was poured into crashed ice, the pH was
adjusted to >
1o 12 with NaOH (iN) and the mixture was extracted three times with EtaO; the
organic
phases were washed with water, dried with MgSO4, filtered and evaporated to
give 1.60 g
of crude product. Purification by flash chromatography on Si02 with a gradient
of n-
heptane: AcOEt (9:1 to 1:1) yielded 1.27 g of 2-methyl-6-(4-trifluoromethyl-
phenyl)-
pyridin-3-ylamine as colorless solid
MS: 253.1 (M+H)+.
The necessarybuilding block [rac]-2-[4-(1-carboxy-ethoxy)-2-methyl-phenoxy]-2-
methyl-propionic acid ethyl ester used in the procedure above was prepared as
follows:
F] f racl -2- f 4-(1-MethoUcarbonyl-ethoxy)-2-methyl-phenoxyl -2-methyl-
propionic acid
ethyl ester
2o A mixture of 3.0 g (12.6 mrrmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-
propionic
acid ethyl ester (described in WO 02/092590), 3.96 m1= 4.51 g (33.2 mmol) of
inethyl-2-
chloro-propionate, 0.42 g (2.5 mmol) of potassium iodide and 8.70 g (63 mmol)
of
K2CO3 in 60 ml of DMF was stirred for 54 h at RT. It was then poured into
crashed ice
and extracted three times with diethylether; the organic phases were washed
with water,
dried with MgSO4i filtered and evaporated to give 4.10 g of the title compound
as yellow
oil.
MS: 324.2 (M)+.
Gl [racl-2-f 4-(1-Carboxy-ethoxy)-2-methyl-phenoxyl-2-methXl-propionic acid
ethyl
ester
3o 4.05 g (12.5 mmol) of [rac]-2-[4-(l-methoxycarbonyl-ethoxy)-2-methyl-
phenoxy]-2-
methyl-propionic acid ethyl ester were dissolved in 100 ml of THF and cooled
down to a
temperature of 2 C. 18.7 znl (18.7 mmol) of a LiOH-solution (1M in water) was
added
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below 5 C. After 3 hours stirring between 2 C and 5 C, the reaction mixture
was poured
into crashed ice and extracted three times with AcOEt; the organic phases were
washed
with water, dried with MgSO4, filtered and evaporated to give 4.8 g of crude
product
which was purified by chromatography over silica gel with a gradient of MeC12
and
MeOH to yield 2.53 g of the title compound as light yellow oil.
MS: 309.2 (M-H)".
Example 6
[rac] -2-{4- [ 1-(Biphenyl-4-ylcarbamoyl)-ethoxy] -2-methyl-phenoxy}-2-methyl-
propionic acid
1o In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-
(1-carboxy-
ethoxy) -2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 5G] )
was
reacted with 4-amino-biphenyl to give [rac]-2-{4-[1-(biphenyl-4-ylcarbamoyl)-
ethoxy]-
2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently
saponified to yield the title compound as colorless solid.
MS: 432.2 (M-H)-.
Exa.mple 7
[rac]-2-(4-{ 1- [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylcarbamoyl]-
ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
carboxy-
2o ethoxy)-2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 5G]
) was
reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylamine
(prepared from 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic
acid (example 1E]) in analogy to the procedures described in examples 5D] and
5E]) to
give [rac]-2-(4-{ 1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylcarbamoyl] -ethoxy}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester,
which
was subsequently saponified to yield the title compound as yellow oil.
MS: 542.2 (M-H)-.
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Examvle 8
[rac]-2-Methyl-2-{2-methyl-4- [ 1-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
ethoxy]-
phenoxy}-propionic acid
A] In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-
(1-
carboxy-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example
5G])
was reacted with 3'-trifluoromethyl-biphenyl-4-ylamine (example 8B]) to give
[rac]-2-
rnethyl-2-[2-methyl-4- [ 1-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-ethoxy]
-
phenoxy]-propionic acid ethyl ester, which was subsequently saponified to
yield the title
compound as colorless foam.
io MS: 500.2 (M-H)-.
The necessary building block 3'-trifluoromethyl-biphenyl-4-ylamine used in the
procedure above was prepared as follows:
Bl 3'-Trifluoromethyl-biphenyl-4-ylamine
3.0 g (13.3 mmol) of4-iodoaniline was dissolved in 40 ml of 1,2-
dimethoxyethane. To
this solution were added 20 ml of water, 2.60 g (13.3 mmol) of 3-
trifluoromethyl-
phenylboronic acid, 2.50 g (22.9 mmol) of anhydrous sodium carbonate and 0.31
g (0.27
mmol) of tetrakis(triphenylphoshine) -palladium (0). This reaction mixture was
stirred at
95 C for 20 hours, then cooled down to RT, filtered and the residue was
washed with
AcOEt. The filtrate was then extracted twice with AcOEt; the organic phases
were washed
with water, dried with MgSO4i filtered and evaporated to give 3.66 g of crude
product
which was purified by chromatography over silica gel with a gradient of n-
heptane and
AcOEt to yield 2.31 g of the title compound as a light brown solid.
MS: 237.8 (M+H)+.
Example 9
[rac]-2-Methyl-2-{2-methyl-4-[1-(4'-trifluoromethyl-biphenyl-3-ylcarbamoyl)-
ethoxy]-
phenoxy}-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
carboxy-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 5G])
was
reacted with 4'-trifluoromethyl-biphenyl-3-ylamine (prepared in analogy to the
procedure described in example 8B]) to give [rac]-2-methyl-2-{2-methyl-4-[1-
(4'-
trifluoromethyl-biphenyl-3-ylcarbamoyl)-ethoxy]-phenoxy}-propionic acid ethyl
ester,
which was subsequently saponified to yield the title compound as colorless
foam.
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MS: 500.2 (M-H)-.
Example 10
2-Methyl-2-(2-methyl-4-{ [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoyl]-methoxy}-phenoxy)-propionic acid
In analogy to the procedures described in example lA] and 1B], 2-(4-
carboxymethoxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-
hydroxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO
02/092590) and
methyl 2-chloro-acetate followed by saponification in analogy to the
procedures
described in examples 5F] and 5G]) was reacted with 2-methyl-6-(4-
trifluoromethyl-
io phenyl)-pyridin-3-ylamine (example 5E] ) to give 2-methyl-2-(2-methyl-4-{
[2-methyl-6-
(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methoxy}-phenoxy)-propionic
acid
ethyl ester, which was subsequently saponified to yield the title compound as
colorless
solid.
MS: 501.2 (M-H)-.
Example 11
2-[4-(Biphenyl-4-ylcarbamoylmethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-(4-
carboxymethoxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-
hydroxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO
02/092590) and
methyl 2-chloro-acetate followed by saponification in analogy to the
procedures
described in examples 5F] and 5G] ) was reacted with 4-amino-biphenyl to give
2-[4-
(biphenyl-4-ylcarbamoylmethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
ethyl
ester, which was subsequently saponified to yield the title compound as
colorless solid.
MS: 418.1 (M-H)-.
Example 12
2-(4-{ [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-
methoxy}-2-methyl-phenoxy)-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-(4-
carboxymethoxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-
hydroxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO
02/092590) and
methyl2-chloro-acetate followed by saponification in analogy to the procedures
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described in examples 5F] and 5G]) was reacted with 4-cyclopropyl-2-(4-
trifluoromethyl-phenyl)-pyrimidin-5-ylamine (prepared from 4-trifluoromethyl-2-
(4-
trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 1E}) in analogy
to the
procedures described in examples 5D] and 5E] ) to give 2-(4-{ [4-cyclopropyl-2-
(4-
trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-methoxy}-2-methyl-phenoxy)-2-
methyl-propionic acid ethyl ester, which was subsequently saponified to yield
the title
compound as light yellow solid.
MS: 528.1(M-H)-.
Example 13
lo 2-Methyl-2-{2-methyl-4-[(3'-trifluoromethyl-biphenyl-4-ylcarbarnoyl)-
methoxy]-
phenoxy}-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-(4-
carboxymethoxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-
hydroxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO
02/092590) and
methyl 2-chloro-acetate followed by saponification in analogy to the
procedures
described in examples 5F] and 5G] ) was reacted with 3'-trifluoromethyl-
biphenyl-4-
ylamine (example 8B)) to give 2-methyl-2-{2-methyl-4-[(3'-trifluoromethyl-
biphenyl-4-
ylcarbamoyl)-methoxy]-phenoxy}-propionic acid ethyl ester, which was
subsequently
saponified to yield the title compound as colorless solid.
MS: 486.3 (M-H)-.
Example 14
2-Methyl-2-{2-methyl-4-[ (4'-trifluoromethyl-biphenyl-3-ylcarbamoyl)-methoxy]-
phenoxy}-propionic acid
In analogy to the procedures described in example lA] and IB], 2-(4-
carboxymethoxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-(4-
hydroxy-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO
02/092590) and
methyl 2-chloro-acetate followed by saponification in analogy to the
procedures
described in examples 5F] and 5G] ) was reacted with 4'-trifluoromethyl-
biphenyl-3-
ylamine (prepared in analogy to the procedure described in example 8B]) to
give 2-
methyl-2-{2-methyl-4-[(4'-trifluoromethyl-biphenyl-3-ylcarbamoyl)-methoxy]-
phenoxy}-propionic acid ethyl ester, which was subsequently saponified to
yield the title
compound as colorless solid.
MS: 486.3 (M-H)'.
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Example 15
2-Methyl-2- (4- { 3- [ 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoyl] -
propyl}-phenoxy)-propionic acid
Al 2-Methyl-2-(4-13- [2-methyl-6- (4-trifluoromethXl-phenyl)-p~tridin-3-
,carbamoyil -
proMll- henoxy)-propionic acid tert-butyl ester
In analogy to the procedure described in example lA], 4-[4-(1-tert-
butoxycarbonyl-l-
methyl-ethoxy)-phenyl]-butyric acid (PCT Int. Appl.(2003), W02003048130A2) was
reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example
5E] ) to
give the title compound as a light yellow solid.
1o MS: 557.5 (M+H)+.
Bl 2-Methyl-2-(4-13-f 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoyll-
propyl}-phenoxyl-propionic acid
0.16 g (0.29 mmol) of 2-methyl-2-(4-{3-[2-methyl-6-(4-trifluoromethyl-phenyl)-
pyridin-3-ylcarbamoyl]-propyl}-phenoxy)-propionic acid tert-butyl ester was
dissolved
in 15 ml of MeC12. 0.09 m1= 0.094 g (0.9 mmol) of anisole was added, followed
by 0.22
m1= 0.33 g (2.9 mmol) of trifluoroacetic acid. The reaction mixture was
stirred at reflux
(oil bath 50 C) for 16 hours. The solvent was removed by evaporation and the
residue
dried in high vacuo for 2 hours. The crude product (0.24 g) was purified by
flash
chromatography (Si02, gradient of MeC12 / MeOH) to give 0.137 g of the title
compound
as an off-white gum.
MS: 499.2 (M-H)-.
Example 16
2- (4-{3- [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-
propyl}-phenoxy)-2-rnethyl-propionic acid
In analogy to the procedures described in example 1A] and 15B], 4-[4-(1-tert-
butoxycarbonyl-l-methyl-ethoxy)-phenyl]-butyric acid (PCT Int. Appl.(2003),
W02003048130A2) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
pyrimidin-5-ylamine (prepared from 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
pyrimidine-5-carboxylic acid (example 1E] ) in analogy to the procedures
described in
examples 5D] and 5E] ) to give 2-(4-{3-[4-cyclopropyl-2-(4-trifluoromethyl-
phenyl)-
pyrimidin-5-ylcarbamoyl)-propyl}-phenoxy)-2-methyl-propionic acid tert-butyl
ester,
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which was subsequently cleaved with trifluoroacetic acid to yield the title
compound as
an off-white foam.
MS: 526.1 (M-H)-.
Exam~le 17
2-Methyl-2-{4-[3-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-propyl]-phenoxy}-
propionic acid
In analogy to the procedures described in example 1A] and 15B], 4-[4-(1-tert-
butoxycarbonyl-l-methyl-ethoxy)-phenyl]-butyric acid (PCT Int. Appl.(2003),
W02003048130A2) was reacted with 3'-trifluoromethyl-biphenyl-4-ylamine
(example
lo 8B]) to give 2-methyl-2-{4-[3-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
propyl]-
phenoxy}-propionic acid tert-butyl ester, which was subsequently cleaved with
trifluoroacetic acid to yield the title compound as a light yellow oil.
MS: 484.3 (M-H)-.
Example 18
2-Methyl-2-{4-[3-(4'-trifluoromethyl-biphenyl-3-ylcarbamoyl)-propyl]-phenoxy}-
propionic acid
In analogy to the procedures described in example IA] and 15B], 4-[4-(1-tert-
butoxycarbonyl-l-methyl-ethoxy)-phenyl]-butyric acid (PCT Int. Appl.(2003),
W02003048130A2) was reacted with 4'-trifluoromethyl-biphenyl-3-ylamine
(prepared
in analogy to the procedure described in example 8B]) to give 2-methyl-2-{4-[3-
(4'-
trifluoromethyl-biphenyl-3-ylcarbamoyl)-propyl]-phenoxy}-propionic acid tert-
butyl
ester, which was subsequently cleaved with trifluoroacetic acid to yield the
title
compound as a light yellow foam.
MS: 484.3 (M-H)-.
Example 19
2-Methyl-2- [2-methyl-4-(2-{ [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-
carbonyl]-amino}-ethoxy)-phenoxy]-propionic acid
A} In analogy to the procedures described in example 1A] and 1B], 2-[4-(2-
amino-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 19C])
was
3o reacted with 2-methyl-6- (4-trifluoromethyl-phenyl) -nicotinic acid
(example 5D] ) to give
2-methyl-2- [2-methyl-4-(2-{ [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-
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carbonyl]-amino}-ethoxy)-phenoxyJ-propionic acid ethyl ester, which was
subsequently
saponified to yield the title compound as colorless solid.
MS: 515.2 (M-H)-.
The necessary building block 2-[4-(2-amino-ethoxy)-2-methyl-phenoxy]-2-methyl-
propionic acid ethyl ester used in the procedure above was prepared as
follows:
Bl 2- ( 4-( 2-tert-ButoxycarbonXlamin o-ethoxy) -2-methyl-phenoxyl -2-methyl-
propionic
acid ethyl ester
3.0 g (12.6 mmol) of 2-(4-hydroxy-2-methyl-pheno7cy)-2-methyl-propionic acid
ethyl
ester (described in WO 02/092590), 2.24 rnl = 2.33 g (14.4 mmol) of N-Boc-
io ethanolamine and 4.43 g (16.9 mmol) of triphenylphosphine were dissolved in
120 ml of
THF. The stirred reaction mixture was cooled down to 0 C and a solution of
3.70 g (15.8
mmol) of di-tert-butyl azodicarboxylate in 30 ml of THF was added drop by
drop. Then,
the reaction mixture was warmed up to ambient temperature. After 20 hours, the
solvent
was evaporated and the residue (16.0 g) was purified by chromatography (Si02,
heptane /
AcOEt = 95:5 to 4:1) to give 4.76 g of the title compound as colorless oil.
MS: 382.3 (M+H)+.
Cl 2-r4-(2-amino-ethoxx)-2-methyl-phenoxyl-2-methyl-propionic acid ethyl ester
1.60 g ( 4.2 mmol) of 2-[4-(2-tert-butoxycarbonylamino-ethoxy)-2-methyl-
phenoxy]-2-
methyl-propionic acid ethyl ester was dissolved in 20 ml of MeC12; 3.21 ml (42
mmol) of
trifluoroacetic acid was added drop by drop. After two hours stirring at RT,
the solvent
was removed by evaporation, the residue was poured into crashed ice, the pH
was
adjusted to >9 with a saturated sodium carbonate solution (in water) and the
mixture
was extracted twice with AcOEt; the organic phases were washed with water,
dried with
MgSO4, filtered and evaporated to give 1.2 g of crude product which was
purified by
chromatography over silica gel with a gradient of MeC12 and MeOH to yield 1.09
g of the
title compound as colorless oil.
MS: 282.2 (M+H)+.
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Exarnnle 20
2- [4-(2- { [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-
amino}-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example lA] and IB], 2-[4-(2-amino-
ethoxy)-
2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 19C] ) was
reacted with
4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(example lE])
to give 2- [4-(2-{ [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which
was
subsequently saponified to yield the title compound as colorless solid.
io MS: 542.2 (M-H)-.
Example 21
2-Methyl-2- [2-methyl-4-(2-{ [4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-
pyrimidine-5-carbonyl]-amino}-ethoxy)-phenoxy]-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-[4-(2-amino-
ethoxy)-
2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 19C] ) was
reacted with
4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(prepared
from ethyl 4,4,4-trifluoroacetoacetate: by i) treatment with triethyl
orthoformate in
analogy to the procedure described in example 1C] to yield 2-[1-ethoxy-meth-
(E,Z)-
ylidene] -4,4,4-trifluoro-3-oxo-butyric acid ethyl ester; ii) condensation
with 4-
(trifluoromethyl)benzamidine hydrochloride in analogy to the procedure
described in
example 1D] to give 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-
5-
carboxylic acid ethyl ester; iii) saponification in analogy to the procedure
described in
example lE] ) to give 2-methyl-2- [2-methyl-4-(2-{ [4-trifluoromethyl-2-(4-
trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethoxy)-phenoxy] -
propionic
acid ethyl ester, which was subsequently saponified to yield the title
compound as
colorless solid.
MS: 570.3 (M-H)-.
Example 22
2- [4-(2-{ [4-Methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-[4-(2-amino-
ethoxy)-
2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 19C] ) was
reacted with
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4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(prepared
from 4-methoxy-3-oxo-butyric acid methyl ester: by i) treatment with triethyl
orthoformate in analogy to the procedure-described in example 1C] to yield 2-
[1-ethoxy-
meth-(E,Z)-ylidene]-4-methoxy-3-oxo-butyric acid methyl ester; ii)
condensation with
4-(trifluoromethyl)benzamidine hydrochloride in analogy to the procedure
described in
example 1D] to give a mixture of 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-
pyrimidine-5-carboxylic acid methyl and ethyl ester; iii) saponification in
analogy to the
procedure described in example lE) ) to give 2- [4-(2-{ [4-methoxymethyl-2-(4-
trifluoromethyl-phenyl) -pyrimidine-5-carbonyl] -amino } -ethoxy)-2-methyl-
phenoxy] -2-
methyl-propionic acid ethyl ester, which was subsequently saponified to yield
the title
compound as colorless oil.
MS: 546.2 (M-H)-.
Example 23
2- [4- (2- {2- [4-Cyclopropyl-2- (4-trifluoromethyl-phenyl)-pyrimidin-5-yl] -
acetylamino }-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
A] In analogy to the procedures described in example lA] and IB], 2-[4-(2-
amino-
ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 19C])
was
reacted with [4-cyclopropyl-2-(4-trifluorornethyl-phenyl)-pyrimidin-5-yl]-
acetic acid
(example 23E]) to give 2-[4-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
pyrimidin-5-yl) -acetylamino}-ethoxy)-2-methyl-phenoxy] -2-methyl-propionic
acid
ethyl ester, which was subsequently saponified to yield the title compound as
colorless
solid.
MS: 556.2 (M-H)-.
The necessary building block [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
pyrimidin-5-
yl] -acetic acid used in the procedure above was prepared as follows:
BI f4-CXclopropyl-2- 4-trifluoromethyl-phenyl)-Mimidin-5-yll-methanol
Within 10 min was dropped 31.6 ml (37.9 mmol) of 1.2 M DIBAL-H solution in
toluene
to a dry ice cooled (-50 C) solution of 4.25 g (12.64 mmol) 4-cyclopropyl-2-
(4-
trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 1D])
in 50 ml
3o of THF. The reaction mixture was stirred 30 min at -50 C and after letting
rise the
temperature to RT, the reaction was stirred for lh at RT. The reaction mixture
was taken
up in ether and washed with 1N HCL and water. The solvent was removed under
reduced
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pressure to give 3.72 g of pure j4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
pyrimidin-
5-yl) -methanol.
MS: 295.1 (M+H)+.
Cl 5-Chloromethyl-4-cXclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine
A mixture of 1.9 g (6.46 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
pyrimidin-5-yl]-methanol and 0.515 ml (7.1 mmol) thionylchloride in 20 ml
dichloromethane was stirred for lh at RT. The reaction mixture was taken up in
ether
and washed with sodium bicarbonate solution and water. The ether phase was
concentrated under reduced pressure to give 1.97 g of pure 5-chloromethyl-4-
io cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
MS: 313.1 (M+H)+.
Dl (4-C~clopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yll-acetonitrile
3.12 g (10.0 mmol) of 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-
phenyl)-
pyrimidine was dissolved in 7 ml of dimethyl sulfoxide; 0.59 g of sodium
cyanide (12
mmol) was added and the mixture was stirred at 40 C for 2 hours. Then, the
reaction
mixture was poured into a mixture of ice and water and the residue formed was
filtered
off. It was subsequently dissolved in tert-butyl methyl ether; the organic
phase was
washed with water, then with brine and dried over anhydrous sodium sulfate.
During
evaporation of the solvent, 1.0 g of the title compound separated as colorless
solid.
2o Another 1.1 g of the title compound could be obtained by chromatography
(Si02) with
dichlormethane as the eluent.
MS: 304.2 (M+H)+.
El (4-CSclopropyl-2-(4-trifluoromethyl-phenXl)-pyrimidin-5-yl]-acetic acid
A mixture of 2.05 g (6.75 mmol) of the above prepared j4-cyclopropyl-2-(4-
trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetonitrile,1.08 g of sodium
hydroxide (27
mmol), 5 ml of water and 25 ml of propanol was stirred vigorously at 100 C.
The
hydrolysis was complete after 2 hours. The reaction mixture was then
evaporated to
dryness and the residue was dissolved in 20 ml of water; then, cold 4 N
aqueous HCI was
added and the compound was extracted with three portions of 25 ml of ethyl
acetate; the
combined organic phases were washed with water and brine, dried over anhydrous
sodium sulfate and evaporated to dryness to yield after crystallization from
ethyl acetate
1.56 g of the title product as colorless solid.
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MS: 643.2 (2M-H)".
Example 24
2-Methyl-2- (2-methyl-4- {2- [ (4'-trifluoromethyl-biphenyl-4-carbonyl)-amino]
-ethoxy}-
phenoxy)-propionic acid
In analogy to the procedures described in example lA] and 1B], 2-[4-(2-amino-
ethoxy)-
2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 19C]) was
reacted with
4'-trifluoromethyl-biphenyl-4-carboxylic acid (prepared in analogy to the
procedure
described in example 3B]) to give 2-methyl-2-(2-methyl-4-{2-[(4'-
trifluoromethyl-
biphenyl-4-carbonyl)-amino]-ethoxy}-phenoxy)-propionic acid ethyl ester, which
was
io subsequently saponified to yield the title compound as colorless oil.
MS: 500.2 (M-H)-.
Example 25
2-Methyl-2-(2-methyl-4-{2- [(3'-trifluoromethyl-biphenyl-4-carbonyl)-amino]-
ethoxy}-
phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-[4-(2-amino-
ethoxy)-
2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 19C] ) was
reacted with
3'-trifluoromethyl-biphenyl-4-carboxylic acid (example 3B]) to give 2-methyl-2-
(2-
methyl-4-{2- [ ( 3'-trifluoromethyl-biphenyl-4-carbonyl)-amino] -ethoxy}-
phenoxy)-
propionic acid ethyl ester, which was subsequently saponified to yield the
title compound
2o as colorless oil.
MS: 500.2 (M-H)-.
Example 26
2- [4- (2-{ [4-Cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]
-amino }-
ethoxy)-2-rnethyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], 2-[4-(2-amino-
ethoxy)-
2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 19C]) was
reacted with
4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid-
(example 2C])
to give 2-[4-(2-{ [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, whichwas
subsequently saponified to yield the title compound as colorless solid.
MS: 542.2 (M-H)-.
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Example 27
[rac]-2- [4-(2-{ [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-1-methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(2-
amino-1-
methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (prepared
from
2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (WO
02/092590)
and [rac]-(2-hydroxy-propyl)-carbamic acid tert-butyl ester [Bioorganic &
Medicinal
Chemistry (1998), 6(12), 2405-2419] in analogy to the procedures described in
examples
19B] and 19C]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-
1o pyrimidine-5-carboxylic acid (example 1E]) to give [rac]-2-[4-(2-{[4-
cyclopropyl-2-(4-
trifluoromethyl-phenyl)-pyrimidine-5-carbonyl] -amino}-1-methyl-ethoxy)-2-
methyl-
phenoxy] -2-methyl-propionic acid ethyl ester, which was subsequently
saponified to
yield the title compound as colorless solid.
MS: 556.1 (M-H)-.
Example 28
[rac] -2- [4- (2- { [4-Cyclopropyl-2- ( 3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-1-methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(2-
amino-1-
methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (prepared
from
2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (WO
02/092590)
and [rac] -(2-hydroxy-propyl)-carbamic acid tert-butyl ester [Bioorganic &
Medicinal
Chemistry (1998), 6(12), 2405-2419] in analogy to the procedures described in
examples
19B] and 19C] ) was reacted with 4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-
pyrimidine-5-carboxylic acid (example 2C] ) to give [rac]-2-[4-(2-{ [4-
cyclopropyl-2-(3-
trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-1-methyl-ethoxy)-2-
methyl-
phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently
saponified to
yield the title compound as colorless solid.
MS: 556.1 (M-H)-.
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Example 29
[rac] -2-Methyl-2-(2-methyl-4-{ 1-methyl-2- [ (3'-trifluoromethyl-biphenyl-4-
carbonyl)-
amino]-ethoxy}-phenoxy)-propionic acid
In analogy to the procedures described in example lA] and 1B], [rac]-2-[4-(2-
amino-1-
methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (prepared
from
2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (WO
02/092590)
and [rac]-(2-hydroxy-propyl)-carbamic acid tert-butyl ester [Bioorganic &
Medicinal
Chemistry (1998), 6(12), 2405-2419] in analogy to the procedures described in
examples
19B] and 19C] ) was reacted with 3'-trifluoromethyl-biphenyl-4-carboxylic acid
(example
lo 3B]) to give [rac]-2-methyl-2-(2-methyl-4-{1-methyl-2-[(3'-trifluoromethyl-
biphenyl-4-
carbonyl)-amino]-ethoxy}-phenoxy)-propionic acid ethyl ester, which was
subsequently
saponified to yield the title compound as colorless solid.
MS: 514.2 (M-H)-.
Example 30
[rac]-2-Methyl-2-(2-methyl-4-{1-methyl-2-[(4'-trifluoromethyl-biphenyl-4-
carbonyl)-
amino]-ethoxy}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(2-
amino-l-
methyl-ethoxy)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (prepared
from
2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (WO
02/092590)
2o and [rac]-(2-hydroxy-propyl)-carbamic acid tert-butyl ester [Bioorganic &
Medicinal
Chemistry (1998), 6(12), 2405-2419] in analogy to the procedures described in
examples
19B] and 19C] ) was reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic acid
(prepared in analogy to the procedure described in example 3B] ) to give [rac]-
2-methyl-
2-(2-methyl-4-{ 1-methyl-2- [ (4'-trifluoromethyl-biphenyl-4-carbonyl)-amino] -
ethoxy}-
phenoxy)-propionic acid ethyl ester, which was subsequently saponified to
yield the title
compound as colorless solid.
MS: 514.2 (M-H)-.
Example 31
[rac]-2- [4-(2-{ [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
3o amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid
A] In analogy to the procedures described in example lA] and 1B], [rac]-2-[4-
(2-amino-
propyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 31E])
was
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reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic acid
(example 1E]) to give [rac]-2-[4-(2-{[4-cyclopropyl-2-(4-trifluoromethyl-
phenyl)-
pyrimidine-5-carbonyl]-amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic
acid
ethyl ester, which was subsequently saponified to yield the title compound as
colorless
solid.
MS: 540.3 (M-H)-.
The necessary building block [rac]-2-[4-(2-amino-propyl)-2-methyl-phenoxy]-2-
methyl-propionic acid ethyl ester used in the procedure above was prepared as
follows:
Bl 2-Methyl-2-f 2-methyl-4 -(3-methyl-3-trimethylsilanyl-oxiranyl)-phenoxyl-
propionic
1o acid ethyl ester (mixture of diast.)
36.1 ml (47.0 mmol) of a sec-butyllithium solution (13M in cyclohexane) was
diluted
with 75 ml of THF and cooled down to - 78 C. A solution of 8.30 ml (47.0
mmol) of (1-
chloroethyl)-trimethylsilane in 30 ml of THF was added drop by drop, followed
by 7.0 ml
(47 mmol) of N,N,N,N-tetramethyl-ethylene-diamine; after stirring for 30 min.
between
- 55 C and - 60 C, the reaction mixture was again cooled down to - 78 C and
a
solution of 7.38 g (29.5 mmol) 2-(4-formyl-2-methyl-phenoxy)-2-methyl-
propionic acid
ethyl ester [PCT Int. Appl.(2003), 98 pp. W02004000762 A2] in 70 ml of THF was
added
and after another 30 min. at - 78 C, it was warmed up to RT. The reaction
mixture was
then poured into crashed ice, the pH was adjusted to about 3 with HCI (1N) and
it was
then extracted twice with AcOEt; the organic phases were washed with water,
dried with
MgSO4, filtered and evaporated to give 10.67 g of crude product which was
purified by
chromatography over silica gel with a gradient of n-heptane and AcOEt to yield
3.40 g of
the title compound as colorless oil.
MS: 350.2 (M)+.
Cl 2-Methyl-2-[2-methyl-4-(2-oxo-propyl)-phenoxy]-propionic acid ethyl ester
3.20 g (9.1 mmol) of 2-methyl-2-[2-methyl-4-(3-methyl-3-trimethylsilanyl-
oxiranyl)-
phenoxy] -propionic acid ethyl ester (mixture of diast.) was dissolved in 30
ml of MeOH;
then, 16 ml (32 mmol) of sulfuric acid (2 molar in water) was added at RT and
after 30
min., the reaction mixture was poured into cold water and extracted twice with
MeC12;
the organic phases were washed with water, dried with MgSO4, filtered and
evaporated to
give 2.66 g of crude product which was purified by chromatography over silica
gel with a
gradient of n-heptane and AcOEt to yield 2.06 g of the title compound as
colorless oil.
MS: 278.2 (M)+.
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Dl 2- (4-f 2-f (E andlor Z)-Hydroxyiminol-propyll-2-methyl-phenoxy)-2-methyl-
propionic acid ethyl ester
2.0 g (7.2 mmol) of 2-methyl-2- [2-methyl-4-(2-oxo-propyl)-phenoxy] -propionic
acid
ethyl ester was dissolved in 20 ml of EtOH; 0.81 g(11.5 mmol) of hydroxylamine-
hydrochloride was added, followed by a solution of 1.79 g (21.6 mmol) sodium
acetate in
20 ml of water. After 2 hours, the solvents were removed by evaporation, the
residue was
dissolved in water and MeC12 and extracted twice with MeC12; the organic
phases were
washed with water, dried with MgSO4, filtered and evaporated to give 2.24 g of
crude
product which was purified by chromatography over silica gel with a gradient
of n-
1o heptane and AcOEt to yield 1.80 g of the title compound as colorless oil.
MS: 293.2 (M)+.
El (racl-2-(4-(2-Amino-propyl)-2-methyl-phenoL[Yl-2-methyl-propionic acid
ethyl ester
1.56 g (5.3 mmol) of 2-(4-{2-[(E and/or Z)-hydroxyimino]-propyl}-2-methyl-
phenoxy)-
2-methyl-propionic acid ethyl ester was dissolved in 50 nzl of glacial acetic
acid;, 0.3 g of
platinum(N)oxide was added and the well stirred mixture was hydrogenated at
RT. After
1 hour, the catalyst was filtered off, washed with AcOH and the solvent
evaporated. The
residue was dissolved in water and MeC12, the pH was adjusted to >12 with NaOH
(2N)
and the mixture was extracted twice with MeC12; the organic phases were washed
with
water, dried with MgSO4, filtered and evaporated to give 1.30 g of crude
product which
was purified by chromatography over silica gel with a gradient of MeC12 and
MeOH to
yield 1.14 g of the title compound as colorless oil.
MS: 280.1 (M+H)+.
Example 32
[rac]-2- [4-(2-{ [4-Cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-propyl)-2-methyl-phenoxy]-2-methyi-propionic acid
In analogy to the procedures described in example 1A] and 1BJ, [rac]-2-[4-(2-
amino-
propyl)-2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 31E] )
was
reacted with 4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic acid
(example 2CJ) to give [rac]-2-[4-(2-{[4-cyclopropyl-2-(3-trifluoromethyl-
phenyl)-
pyrimidine-5-carbonyl] -amino}-propyl)-2-methyl-phenoxy] -2-methyl-propionic
acid
ethyl ester, which was subsequently saponified to yield the title compound as
colorless
solid.
MS: 540.3 (M-H)-.
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Example 33
[rac]-2-Methyl-2-(2-methyl-4-{2-[ (3'-trifluoromethyl-biphenyl-4-carbonyl)-
arnino]-
propyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(2-
amino-
propyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 31E])
was
reacted with 3'-trifluoromethyl-biphenyl-4-carboxylic acid (example 3B] ) to
give [rac]-2-
methyl-2- (2-methyl-4- {2- [ (3'-trifluoromethyl-biphenyl-4-carbonyl)-amino] -
propyl}-
phenoxy)-propionic acid ester, which was subsequently saponified to yield the
title
compound as colorless solid.
io MS: 498.2 (M-H)-.
Examlpe34
[rac]-2-Methyl-2-(2-methyl-4-{2- [(4'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-
propyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(2-
amino-
propyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 31E])
was
reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic acid (prepared in
analogy to the
procedure described in example 3B]) to give [rac]-2-methyl-2-(2-methyl-4-{2-
[(4'-
trifluoromethyl-biphenyl-4-carbonyl)-amino] -propyl.}-phenoxy)-propionic acid
ethyl
ester, which was subsequently saponified to yield the title compound as
colorless solid.
MS: 498.1 (M-H)-.
Examj2le 35
[rac]-2- [4- (1-{ [4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl] -
amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid
A] In analogy to the procedures described in example 1A] and 1B], [rac] -2-[4-
(1-amino-
propyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 35G])
was
reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic acid
(example 1E]) to give [rac]-2-[4-(1-{[4-cyclopropyl-2-(4-trifluoromethyl-
phenyl)-
pyrimidine-5-carbonyl] -amino}-propyl)-2-methyl-phenoxy] -2-methyl-propionic
acid
ethyl ester, which was subsequently saponified to yield the title compound as
light yellow
solid.
MS: 540.5 (M-H)-.
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The necessary building block [rac]-2-[4-(1-amino-propyl)-2-methyl-phenoxy] -2-
methyl-propionic acid ethyl ester used in the procedure above was prepared as
follows:
B 1 3-Methyl-4- ( 2-trimethylsilanyl-ethoxymethoxy) -b enzaldehyde
5.12 g (37.6 mmol) of 3-methyl-4-hydroxy-benzaldehyde was dissloved in 250 ml
of
MeC12; 19.7 ml = 14.9 g (112.8 mmol) of N-ethyl-diisopropylamine was added at
RT,
then, 8.85 ml = 8.36 g (45.1 mmol) of 2-(trimethylsilyl)ethoxymethyl chloride
was added
drop by drop below 25 C. After 5 hours, the reaction mixture was poured into
crashed
ice and the product was extracted twice with MeC12, the organic phases were
washed with
water, dried with MgSO4, filtered and evaporated to give 11.59 g of crude
product which
lo was purified by chromatography over silica gel with a gradient of n-heptane
and AcOEt
to yield 10.61 g of the title compound as light yellow oil.
MS: 208.1 (M-C3H6O)+.
Cl [racl-l-(3-Methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyll-propan-l-ol
9.60 g (36.0 mmol) of 3-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-
benzaldehyde was
dissolved in 350 ml of THF and cooled down to - 70 C; to the stirred
solution, 86.4 ml
(43.2 mmol) of ethyl-lithium solution (0.5 molar in benzene) was added within
30 min.
and then, the reaction mixture was warmed up to RT. After 5 hours, it was
hydrolized by
addition of 50 ml HCl (2N), then diluted with water and AcOEt and extracted
twice with
AcOEt; the organic phases were washed with water, dried with MgSO4, filtered
and
2o evaporated to give 11.68 g of crude product which was purified by
chromatography over
silica gel with a gradient of n-heptane and AcOEt to yield 7.16 g of the title
compound as
light yellow oil.
MS: 296.2 (M)+.
Dl 1- f 3-Methyl-4- (2-trimethylsilanyl-ethoxymetho2cy)-phenyll -propan-l-one
6.15 g (20.7 mmol) of [rac]-1-[3-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-
phenyl)-
propan-l-ol, 0.033 g (0.2 mmol) of TEMPO (2,2,6,6-tetramethyl-l-
piperidinyloxy, free
radical) and 0.135 g (0.4 mmol) of tetrabutylammonium bromide were dissolved
in 150
ml of MeC12. After cooling down to 0 C, a solution of 6.14 g (24.9 mmol) of m-
chloro-
perbenzoic acid in 100 ml of MeC12 was added below 3 C within 30 min.; the
reaction
was then warmed up to RT and after 16 hours, the solvent was removed by
evaporation.
The residue (11.32 g) was purified by chromatography over silica gel with a
gradient of n-
heptane and AcOEt to give 1.20 g of the title compound as yellow oil.
MS: 294.4 (M)+.
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E] 1-(4-H dro_xy-3-meth ~1-phenyl)-propan-1-one
1.17 g (4.0 mmol) of 1-[3-methyl-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-
propan-l-one was dissolved in 30 ml of EtOH; while stirring, 1.86 ml (12
mrnol) of a
HCl-solution (6.4 molar in EtOH) was added and after 2 hours, the solvent was
removed
by evaporation and the residue was partitioned between water and MeC12 and
extracted
twice with MeC12; the organic phases were then washed with water, dried with
MgSO4,
filtered and evaporated to give 0.73 g of crude product as a light brown
solid.
MS: 165.4 (M+H)+.
FI 2-Methyl-2-(2-methyl-4-propionyl-phenoxX)-propionic acid ethyl ester
0.71 g (4.3 mmol) of 1-(4-hydroxy-3-methyl-phenyl)-propan-1-one was dissolved
in 30
ml of acetonitrile, 2.42 g (17.3 mmol) of potassium carbonate was added,
followed by
1.99 m1= 2.61 g (13 mmol) of ethyl 2-bromoisobutyrate. The reaction mixture
was then
heated at reflux for 7 hours. After cooling down to RT, the reaction mixture
was poured
into crashed ice and the product was extracted twice with AcOEt; the organic
phases were
washed with water, dried with MgSO4, filtered and evaporated to give 1.057 g
of crude
product which was purified by chromatography over silica gel with a gradient
of n-
heptane and AcOEt to yield 0.848 g of the title compound as light yellow oil.
MS: 278.2 (M)+.
Gl fracl-2-[4-(1-Amino-propyl)-2-methyl-phenoxy_1-2-methyl-propionic acid
ethxl ester
In analogy to the procedures described in example 31D] and 31E], 2-methyl-2-(2-
rnethyl-4-propionyl-phenoxy)-propionic acid ethyl ester has been converted
into 2-(4-
{1-[(E and/or Z)-hydroxyimino]-propyl}-2-methyl-phenoxy)-2-methyl-propionic
acid
ethyl ester and subsequently hydrogenated to give the title compound as a
light yellow
solid.
MS: 263.2 (M-NH3 +H) +.
Exam lp e 36
[rac]-2- [4-(1-{ [4-Cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl]-
amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac] -2- [4-
(1 -amino-
3o propyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example
35G]) was
reacted with 4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic acid
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(example 2C]) to give [rac]-2-[4-(1-{[4-cyclopropyl-2-(3-trifluoromethyl-
phenyl)-
pyrimidine-5-carbonyl]-amino}-propyl)-2-methyl-phenoxy]-2-methyl-propionic
acid
ethyl ester, which was subsequently saponified to yield the title compound as
light yellow
amorphous solid.
MS: 540.4 (M-H)-.
Example 37
[rac]-2-Methyl-2-(2-methyl-4-{ 1- [ (3'-trifluoromethyl-biphenyl-4-carbonyl)-
amino]-
propyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
amino-
io propyl)-2-methyl-phenoxy]-2-rnethyl-propionic acid ethyl ester (example
35G]) was
reacted with 3'-trifluoromethyl-biphenyl-4-carboxylic acid (example 3B] ) to
give [rac] -2-
methyl-2-(2-methyl-4-{ 1-[ (3'-trifluoromethyl-biphenyl-4-carbonyl) -amino] -
propyl}-
phenoxy)-propionic acid ethyl ester, which was subsequently saponified to
yield the title
compound as light yellow solid.
MS: 498.1 (M-H)-.
Examyle 38
[rac] -2-Methyl-2- (2-methyl-4- { 1- [ (4'-trifluoromethyl-biphenyl-4-
carbonyl)-amino] -
propyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
amino-
propyl)-2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 35G] )
was
reacted with 4'-trifluoromethyl-biphenyl-4-carboxylic acid (prepared in
analogy to the
procedure described in example 3B]) to give [rac]-2-methyl-2-(2-methyl-4-{1-
[(4'-
trifluoromethyl-biphenyl-4-carbonyl)-amino]-propyl}-phenoxy)-propionic acid
ethyl
ester, which was subsequently saponified to yield the title compound as light
yellow solid.
MS: 498.1 (M-H)-.
Example 39
[rac] -2-Methyl-2- (2-methyl-4- { 1-methyl-2- [2-methyl-6- (4-trifluoromethyl-
phenyl)-
pyridin-3-ylcarbamoyl]-ethyl}-phenoxy)-propionic acid
A] In analogy to the procedures described in example lA] and 1B], [rac]-3-[4-
(1-
3o ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phenyl]-butyric acid (example
39D]) was
reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example
5E]) to
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give [rac]-2-methyl-2-(2-methyl-4-{1-methyl-2-[2-methyl-6-(4-trifluoromethyl-
phenyl)-pyridin-3-ylcarbamoyl]-ethyl}-phenoxy)-propionic acid ethyl ester,
which was
subsequently saponified to yield the title compound as colorless solid.
MS: 513.3 (M-H)-.
The necessary building block [rac]-3-[4-(1-ethoxycarbonyl-l-methyl-ethoxy)-3-
methyl-
phenyl]-butyric acid used in the procedure above was prepared as follows:
B1 (E and/or Z)-3-f4-(1-Ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phen-Y-ll-but-
2-
enoic acid ethyl ester
12.49 ml = 13.99g (60.5 mmol) of triethyl phosphonoacetate was diluted with
100 ml of.
1o dioxane under an argon atmosphere and cooled down to 10 C; 1.98 g (45.4
mmol) of
sodium hydride (55 % dispersion in mineral oil) was then added in small
portions. After
min., a solution of 4.0 g (15.1 mmol) of 2-(4-acetyl-2-methyl-phenoxy)-2-
methyl-
propionic acid ethyl ester [PCT Int. Appi. (2002), 35 pp. WO 2002096894A1] in
60 ml of
dioxane was added and the mixture then stirred at reflux for 6 hours. After
cooling down
15 to RT, the reaction mixture was poured into crashed ice, the pH was
adjusted to about 2
with HCl (2N) and it was then extracted twice with AcOEt; the organic phases
were
washed with water, dried with MgSO4i filtered and evaporated to give 12.3 g of
crude
product which was purified by chromatography over silica gel with a gradient
of n-
heptane and AcOEt to yield 4.78 g of the title compound as colorless oil.
MS: 334.2 (M)+.
Cl fracl-3-f4-(1-Ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phenyll-but,yric
acid ethvl
ester
4.70 g (14.1 mmol) of (E and/or Z)-3-[4-(1-ethoxycarbonyl-l-methyl=ethoxy)-3-
methyl-
phenyl]-but-2-enoic acid ethyl ester was dissolved in 150 inl of THF; 0.94 g
of palladium
(10% on activated carbon) was added and the well stirred mixture was
hydrogenated at
RT. After 1 hour, the catalyst was filtered off, washed with THF and the
filtrate was
evaporated to give 4.85 g of crude product which was purified by
chromatography over
silica gel with a gradient of n-heptane and AcOEt to yield 4.60 g of the title
compound as
colorless oil.
MS: 336.2 (M)+.
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D] fracl-3-[4-(1-Ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phenyl]-butXric acid
1.50 g (4.5 mmol) of [rac]-3-[4-(1-ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-
phenyl]-
butyric acid ethyl ester was dissolved in 50 ml of a mixture of THF I MeOH
(7:3); 4.46 ml
(4.46 mmol) of a LiOH-solution (1M in water) was added at RT and the mixture
stirred
for 8 hours. The reaction mixture was then poured into crashed ice, the pH was
adjusted
to about 2 with HCl (2N) and it was extracted twice with MeC12; the organic
phases were
washed with water, dried with MgSO4i filtered and evaporated to give 1.40 g of
crude
product which was purified by chromatography over silica gel with a gradient
of MeC12
and MeOH to yield 0.49 g of the title compound as colorless oil.
io MS: 307.2 (M-H)-.
Example 40
[rac] -2- (4-{2- [4-Cyclopropyl-2-(4-trifl.uoromethyl-phenyl)-pyrimidin-5-
ylcarbamoyl] -
1-methyl-ethyl}-2-methyl-phenoxy)-2-methyl-propionic acid
In analogy to the procedures described in example 1A] and IB], [rac]-3-[4-(1-
ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phenyl]-butyric acid (example 39D])
was
reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylamine
(prepared from 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic
acid (example 1E] ) in analogy to the procedures described in examples 5D] and
5E] ) to
give [rac] -2-(4-{2- [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
2.o ylcarbamoyl]-1-methyl-ethyl}-2-rnethyl-phenoxy)-2-methyl-propionic acid
ethyl ester,
which was subsequently saponified to yield the title compound as colorless
solid.
MS: 540.4 (M-H)-.
Exam ly 41
[rac] -2-Methyl-2- {2-methyl-4- [ 1-methyl-2- (4'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethyl]-phenoxy}-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-3-[4-(1-
ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phenyl]-butyric acid (example 39D])
was
reacted with 4'-trifluoromethyl-biphenyl-4-ylamine (prepared in analogy to the
procedure described in example 8B)) to give [rac]-2-methyl-2-{2-methyl-4-[1-
methyl-2-
(4'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-ethyl]-phenoxy}-propionic acid
ethyl ester,
which was subsequently saponified to yield the title compound as colorless
solid.
MS 498.2 (M-H)-.
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Example 42
[rac]-2-Methyl-2- {2-methyl-4- [ 1-methyl-2- (3'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethyl]-phenoxy}-propionic acid
In analogy to the procedures described in example 1A] and 1B), [rac]-3-[4-(1-
ethoxycarbonyl-l-methyl-ethoxy)-3-methyl-phenyl]-butyric acid (example 39D])
was
reacted with 3'-trifluoromethyl-biphenyl-4-ylamine (example 8B]) to give [rac]-
2-
methyl-2-{2-methyl-4- [ 1-methyl-2-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
ethyl] -
phenoxy}-propionic acid ethyl ester, which was subsequently saponified to
yield the title
compound as colorless solid.
MS: 498.1 (M-H)-.
Example 43
[rac] -2- (4- { 1- [4- Cyclopropyl-2- (4-trifluoromethyl-phenyl) -pyrimidin-5-
ylcarbamoyl] -
ethyl}-2-methyl-phenoxy)-2-methyl-propionic acid
A] In analogy to the procedures described in example 1A] and 1B), [rac]-2-[4-
(1-
carboxy-ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example
43D])
was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrirnidin-5-
ylamine
(prepared from 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic
acid (example lE) ) in analogy to the procedures described in examples 5D] and
5E] ) to
give [rac]-2-(4-{ 1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylcarbamoyl]-ethyl}-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester,
which was
subsequently saponified to yield the title compound as colorless solid.
MS: 526.1 (M-H)-.
The necessary building block [rac] -2- [4-(1-carboxy-ethyl)-2-methyl-phenoxy] -
2-
methyl-propionic acid ethyl ester used in the procedure above was prepared as
follows:
B1 2- f4-((EIZ)-2-Methoxy-l-methyl-vinyl)-2-methyl-phenoxyl-2-meftl-uropionic
acid
eth 1 ester
8.41 g (23.8 mmol) of (methoxymethyl)triphenylphosphonium chloride was
suspended
in 100 ml of THF; after cooling down to - 20 C, 2.74 g (23.8 mmol) of
potassium tert-
butoxide was added in small portions. After 30 min., a solution of 5.20 g
(19.7 mmol) of
2-(4-acetyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int.
Appl.(2002), 35 pp. WO 2002096894A1] in 70 ml of THF was added drop by drop.
After
stirring for 1 hour at - 20 C, the reaction mixture was warmed up slowly to
RT. After
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stirring at RT for 20 hours, the mixture was poured into crashed ice and
extracted twice
with AcOEt; the organic phases were washed with water, dried with MgSO4i
filtered and
evaporated to give 11.40 g of crude product which was purified by
chromatography over
silica gel with a gradient of n-heptane and AcOEt to yield 4.91 g of the title
compound as
colorless oil.
MS: 292.2 (M)+.
Cl fracl-2-Methyl-2-f2-methyl-4-(1-methyl-2-oxo-ethyl)-phenoxyl-prouionic acid
etly
l
ester
4.58 g (15.7 mmol) of 2-[4-((E/Z)-2-methoxy-l-methyl-vinyl)-2-methyl-phenoxy]-
2-
1o methyl-propionic acid ethyl ester was dissolved in 50 ml of THF; while
stirring, 9,4 ml
(18.8 mmol) of HCl (2.ON) was added and the reaction mixture heated up to
reflux for 6
hours. Then, it was cooled down to 0 C, neutralized with sodium hydrogen
carbonate
solution and extracted twice with MeC12; the organic phases were washed with
water,
dried with MgSO4i filtered and evaporated to give 3.89 g of crude product
which was
purified by chromatography over silica gel with a gradient of n-heptane and
AcOEt to
yield 3.13 g of the title compound as colorless oil.
MS: 278.2 (M)+.
DI fracl-2-[4-(1-Carboxy-ethyl)-2-methyl-phenoxy]-2-methXl-propionic acid
ethyl ester
2.78 g (10.0 mmol) of [rac]-2-methyl-2-[2-methyl-4-(1-methyl-2-oxo-ethyl)-
phenoxy]-
propionic acid ethyl ester was dissolved in 40 ml of 2-methyl-2-propanol; 6.25
ml = 4.12
g (50.0 mmol) of 2-methyl-2-butene was added and the reaction mixture was
cooled
down to 15 C. A solution of 3.46 g (26.0 mmol) of sodium chlorite and 2.38 g
(15.0
mmol) of sodium dihydrogenphosphate-dihydrate in 25 ml of water was added drop
by
drop. After stirring for 20 hours at RT, the reaction mixture was poured into
crashed ice
and extracted twice with AcOEt; the organic phases were washed with water,
dried with
MgSO4, filtered and evaporated to give 3.55 g of crude product which was
purified by
chromatography over silica gel with a gradient of n-heptane and AcOEt to yield
2.33 g of
the title compound as light yellow oil.
MS: 293.2 (M-H)-.
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Example 44
[rac] -2-Methyl-2- (2-methyl-4-{ 1- [ 2-methyl-6- (4-trifluoromethyl-phenyl)-
pyridin-3-
ylcarbamoyl]-ethyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
carboxy-
ethyl) -2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 43D])
was
reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example
5E] ) to
give [rac] -2-methyl-2-(2-methyl-4-{ 1-[2-methyl-6-(4-trifluoromethyl-phenyl)-
pyridin-
3-ylcarbamoyl]-ethyl}-phenoxy)-propionic acid ethyl ester, which was
subsequently
saponified to yield the title compound as light yellow solid.
l0 MS: 499.1 (M-H)-.
Example45
[rac]-2-Methyl-2-{2-methyl-4-[ 1-(4'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-
ethyl]-
phenoxy}-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
carboxy-
ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester (example 43D])
was
reacted with 4'-trifluoromethyl-biphenyl-4-ylamine (prepared in analogy to the
procedure described in example 8B]) to give [rac]-2-methyl-2-{2-methyl-4-[1-
(4'-
trifluoromethyl-biphenyl-4-ylcarbamoyl)-ethyl]-phenoxy}-propionic acid ethyl
ester,
which was subsequently saponified to yield the title compound as light yellow
solid.
MS: 484.3 (M-H)-.
Example 46
[rac] -2-Methyl-2-{2-methyl-4- [ 1- (3'-trifluoromethyl-biphenyl-4-
ylcarbamoyl)-ethyl]-
phenoxy}-propionic acid
In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-(1-
carboxy-
ethyl)-2-methyl-phenoxy] -2-methyl-propionic acid ethyl ester (example 43D] )
was
reacted with 3'-trifluoromethyl-biphenyl-4-ylamine (example 8B]) to give [rac]-
2-
methyl-2-{2-methyl-4- [ 1-(3'-trifluoromethyl-biphenyl-4-ylcarbamoyl)-ethyl] -
phenoxy}-
propionic acid ethyl ester, which was subsequently saponified to yield the
title compound
as light yellow foam.
MS: 484.3 (M-H)-.
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Exarn ln e 47
[rac]-2-Methyl-2-[2-methyl-4-(1-{ [2-(4-trifluoromethoxy-phenyl)-4-
trifluoromethyl-
pyrimidine-5-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid
A] In analogy to the procedures described in example 1A] and 1B], [rac]-2-[4-
(1-amino-
ethyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester [PCT Int.
Appl.(2002), 35
pp. WO 2002096894A1] was reacted with 2-(4-trifluoromethoxy-phenyl)-4-
trifluoromethyl-pyrimidine-5-carboxylic acid (example 47C]) to give [rac]-2-
methyl-2-
[2-methyl-4-(1-{ [2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-
carbonyl]-amino[-ethyl)-phenoxy]-propionic acid ethyl ester, which was
subsequently
io saponified to yield the title compound as colorless oil.
MS: 570.5 (M-H)-.
The necessary building block 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-
pyrimidine-5-carboxylic acid used in the procedure above was prepared as
follows:
B1 2-(4-Trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic
acid ethXl
ester
A solution of 0.21 g (0.30 mmol) bis(triphenylphosphine)palladium(II)chloride,
2.55 g
(10 mmol) ethyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate and 2.68 g
(13
mmol) of 4-(trifluoromethoxy)phenylboronic acid in 50 ml degassed toluene was
treated
with 10 ml aqueous 2M K3PO4 solution and heated at 80 C for 20h. The reaction
was
cooled to RT and extracted with saturated aqueous NaCI (0 C)/EtaO (3x). The
organic
phases were washed with H20, aqueous 10% NaCl, dried (Na2SO4) and evaporated.
Purification by flash-chromatography on silica gel (heptane/ether 98:2 to
96:4) gave 1.78
g of the title compound as an off-white powder.
MS: 379.9 (M)+.
Cl 2-(4-Trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic
acid
In analogy to the procedure described in example 1E], saponification of 2-(4-
trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl
ester
gave the title compound as a white powder.
MS: 351.1 (M-H)-.
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Exam lu e A
Film coated tablets containing the following ingredients can be manufactured
in a
conventional manner:
Ingredients Per tablet
Kernel:
Compound of formula (I) 10.0 mg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
Povidone K30 12.5 mg 15.0 mg
Sodium starch glycolate 12.5 mg 17.0 mg
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glyco16000 0.8 mg 1.6 mg
Talc 1.3 mg 2.6 mg
Iron oxide (yellow) 0.8 mg 1.6 mg
Titan dioxide 0.8 mg 1.6 mg
The active ingredient is sieved and mixed with microcrystalline cellulose and
the
mixture is granulated with a solution of polyvinylpyrrolidone in water. The
granulate is
mixed with sodium starch glycolate and magnesiumstearate and compressed to
yield
kernels of 120 or 350 mg respectively. The kernels are lacquered with an
aqueous solution
/ suspension of the above mentioned film coat.
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Example B
Capsules containing the following ingredients can be manufactured in a
conventional manner:
Ingredients Per capsule
Compound of formula (I) 25.0 mg
Lactose 150.0 mg
Maize starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the foltowing composition:
Compound of formula (I) 3.0 mg
Gelatine 150.0 mg
Phenol 4.7 mg
Sodium carbonate to obtain a final pH of 7
Water for injection solutions ad 1.0 ml
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Examule D
Soft gelatin capsules containing the following ingredients can be manufactured
in a
conventional manner:
Capsule contents
Compound of formula (I) 5.0 mg
Yellow wax 8.0 mg
Hydrogenated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oil 110.0 mg
Weight of capsule contents 165.0 mg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karion 83 8.0 mg (dry matter)
Titan dioxide 0.4 mg
Iron oxide yellow 1.1 mg
s The active ingredient is dissolved in a warm melting of the other
ingredients and
the mixture is filled into soft gelatin capsules of appropriate size. The
filled soft gelatin
capsules are treated according to the usual procedures.
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Example E
Sachets containing the following ingredients can be manufactured in a
conventional manner:
Compound of formula (I) 50.0 mg
Lactose, fine powder 1015.0 mg
Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidone K 30 10.0 mg
Magnesiumstearate 10.0 mg
Flavoring additives 1.0 mg
The active ingredient is mixed with lactose, microcrystalline cellulose and
sodium
carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone
in water.
The granulate is mixed with magnesiumstearate and the flavouring additives and
filled
into sachets.
